Jeffrey Lieberman, MD: Esketamine for Psychiatric Indications


Ketamine looks promising as a potential therapy for treatment-resistant depression. The problem is that more research is needed to understand it.

Last week, the US Food and Drug Administration (FDA) Psychopharmacologic Drug Advisory Committee and Drug Safety and Risk Management Advisory Committee voted 14-2, with 1 abstention, to support the clinical profile of esketamine (Spravato) nasal spray as a potential therapy for treatment-resistant depression.

Jeffrey Lieberman, MD, agreed with the committee’s decision to support the esketamine’s therapeutic potential, which precedes the drug’s New Drug Application consideration by the FDA in a few weeks. But he didn’t feel as certain regarding the drug’s finer details.

In an interview with MD Magazine®, Lieberman, the Chair and Professor of Psychiatry at the Columbia University College of Physicians and Surgeons, explained how the potentially impeding approval of esketamine could force physicians to improvise dosing and continuation early into the first prescribing phase of in-need patients with depression.

MD Mag: What are the potential benefits of esketamine and its mechanism of action?

Lieberman: Anti-depressive pharmacologic treatment has historically focused on the neurotransmitters of norepinephrine and serotonin, and virtually all of the marketed and clinically effective antidepressants are variations on selective serotonin reuptake inhibitors, selective norepinephrine selective, or combined SNRIs.

There's been efforts—intensive, numerous efforts made by companies and researchers—to identify novel mechanisms of action like CRF antagonists or the neurokinin subtype 1 receptor antagonist, but none has been successful.

There was a serendipitous finding of the effect of ketamine, a drug that's used parentally as a dissociative anesthetic mostly in children or burn victims to treat treatment-resistant depression. And the effects were dramatic—dramatically therapeutic. So, in the wake of that observation and publication, there was an effort to try and develop more easily administrable forms of ketamine and esketamine is the result of that.

Janssen has developed it as an intranasal inhalant form that could be administered non-invasively on a frequent basis, and so it now offers another means—more practical means—to use this really groundbreaking, new therapeutic mechanism for depression. The problem is that—and I'm not complaining—it's been developed and now could be approved by the FDA for marketing and clinical use, but the research base on which we have definitive data to demonstrate the exact dosing parameters, the frequency administration, the duration of how long it should be administered, and what are the relative safety issues have not been identified. They have not been studied.

And it's a question of practice leaping ahead of research, because research takes a long time to do and is dependent on funding, availability, and the NIH is not funding very much and the pharmaceutical companies are funding only limited things that are in their specific product development interest. So it falls to Janssen and J&J to now fund phase 4 studies which would determine who should get it, what are the optimal doses, modes of administration, and how long should they take it.

If somebody has treatment-resistant depression, historically, after medications have failed they've gone to ECT. Now, they have ketamine. And if ketamine works, then the question is, well, what's the continuation treatment? Do you switch to an SSRI or an SNRI? Do you keep taking ketamine on a regular basis? And if you do ketamine on a regular basis—again, the dosing frequency duration questions have not been answered.

So the doctors are out there on their own trying to improvise, which is understandable. And they'll do in a very judicious way, I'm sure. But the problem is that would be better, if we were guided by data and had clearly developed treatment guidelines.

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