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For patients with treatment-resistant depression (TRD), ketamine and esketamine have offered something that conventional antidepressants often cannot: relief that can arrive quickly. But that speed has come with practical and clinical constraints — dissociation, cardiovascular risks, abuse concerns, and the need for supervised administration.

Now an extended-release oral ketamine tablet in late-stage development is testing whether some of those constraints can be stripped away. KET01, a prolonged-release ketamine hydrochloride formulation, is being studied as an add-on treatment that could potentially be taken at home, with fewer acute dissociative and cardiovascular effects than currently available ketamine-based options.

If the promise holds, the drug could broaden access for patients with TRD across Europe. But experts say the same features that make the tablet attractive — lower peak exposure, fewer subjective effects, and possible home use — also raise questions about dosing, durability, abuse potential, and whether blunting the ketamine experience could blunt part of its therapeutic value.

TRD affects an estimated 20%-30% of patients across the EU. It is broadly defined as the failure to respond adequately to several different antidepressants despite an adequate treatment trial and adherence. TRD has been associated with a 17% increased risk for all-cause mortality, almost a twofold elevated risk for suicide, and a 27% increased risk for death due to accidental overdose.

In the EU, ketamine; generic esketamine; and single-molecule, purified esketamine hydrochloride — all requiring post-administration clinical supervision — are being used on- and off-label to treat these patients.

“From what we see from studies we’ve done so far, KET01, which provides rapid antidepressant effects, acts like a booster to selective serotonin reuptake inhibitors (SSRIs), something that people have been looking for a long time,” Maximilian Doebler, MD, chief business officer of HMNC Brain Health in Munich, Germany, told Medscape News Europe.

“We are also considering a new treatment regimen where, like intranasal esketamine, you dose it three times per week in the beginning, and then two times, etc., vs daily,” he said.

The Promise of KET01

KET01 was developed on the premise that prolonged release allows the active ingredient to reach peak concentration over 6-7 hours, significantly reducing cardiovascular risks, such as increased blood pressure and heart rate, dissociative effects, and abuse potential.

Dissociation is “discontinuity in the normal integration of consciousness, memory, identity, emotion, perception, body representation, motor control, and behavior.”

By removing tolerability issues from the equation, it could also reduce or eliminate the need for clinical supervision during administration as well as frequent, return visits to the clinic.

Phase 2 randomized controlled trial (RCT) findings (KET01) have suggested KET01 240 mg daily for 14 days provided rapid antidepressant efficacy in patients with TRD (n = 27) relative to 160 mg or placebo daily. 

In a second phase 2 RCT (KET02), KET01 240 mg showed stable Clinician-Administered Dissociative States Scale scores over 24 hours compared with intranasal esketamine 84 mg, which produced a pronounced dissociation signal at 40 minutes.

KET01 also demonstrated a lower peak blood concentration of ketamine and higher exposures of the norketamine/hydroxynorketamine metabolite, which, respectively, are believed to influence behavioral and antidepressant properties. In turn, acute heart rate and blood pressure effects were attenuated. 

Thus far only a small number of patients (180) have received the drug, so the data should be interpreted cautiously. However, KET01 qualities are ultimately intended to drive take-at-home, add-on dosing and broaden availability, accessibility, and demand. 

Does the Experience Matter?

Lowan Han Stewart, MD, a specialist in emergency medicine, medical director of Axonklinikken in Oslo, and medical advisor to the PsykForsk Center for Innovative Clinical Research at the Østfold Hospital Trust in Grålum, both in Norway, said he believed that having an oral formulation that can be taken at home is a good concept in terms of greater accessibility, especially for patients requiring maintenance treatment or experiencing remission. 

But he questioned whether it is possible to gain antidepressant effects without the subjective experience.

“Most of the original research looking at subjective experiences measured dissociation, not what we consider the psychedelic components of that experience,” said Stewart. 

Though clinicians believe there is added value to the psychedelic experience, Stewart noted that the value may not be picked up by depression scores. Data have also suggested that statistically significant changes in the Clinician-Administered Dissociative States Scale might explain only a fraction of different responses to ketamine.

“The factor most associated with positive outcomes is an experience of awe, the profound sense of feeling like you are part of something larger. We call this ‘oceanic boundlessness’ — the experience that you are not just a wave in the ocean, but you’re part of the ocean,” he said.

Stewart recalled a patient with severe TRD, suicidality, and chronic posttraumatic stress disorder (PTSD) who had tried antidepressants, 7 years of psychotherapy, trauma treatment, and more and was referred to his clinic through Norway’s public system. The patient developed PTSD as the result of a combat experience during which he was shot, but his friend was killed. He blamed himself.

“During his first treatment, he described dissolving into the universe and becoming one with God and connected to his friend who had died. His friend forgave him, he forgave himself, and when he woke up, he was in complete remission from depression, suicidality, and PTSD and remained in remission as long as I followed him,” said Stewart.

“One of the big questions about this pill is if you’re never going to have a psychedelic experience, are you going to get as much out of it in the long term? You might not be depressed, but will you lose out on meaning and quality of life and sense of hope and well-being?”

“Sometimes we hear from patients that during these sessions, they have new insights into themselves or their illness,” said Jolien Veraart, MD, PhD, psychiatrist and senior scientist at PsyQ Haaglanden at Parnassia Psychiatric Institute in The Hague and the Psychedelic Treatment and Mechanisms research group of the University Center of Psychiatry at the University Medical Center Groningen in Groningen, both in Netherlands.

“They seem to have more cognitive flexibility, which could possibly be part of the therapeutic effect. It’s still up for debate,” she said.

Taking It Home

What happens when you remove the guardrails and move ketamine therapy into the home?

Currently, Veraart does send patients home with an oral esketamine but only after several sessions of clinical supervision. One of her primary concerns with a prolonged-release formulation is dosing.

“It’s still up for debate whether we need high peak concentrations to achieve antidepressant effects,” she said.

“For example, our clinical trials with generic oral esketamine showed antidepressant effects were related to higher doses and individual vs fixed titration. The same has been seen in studies with intranasal esketamine and subcutaneous racemic ketamine: Flexible dosing has appeared to be the most effective strategy.”

“This makes me a little bit skeptical about a prolonged-release formulation,” said Veraart.

Veraart acknowledged the practicality and “patient-friendliness” of the take-home option but noted that certain patients are more sensitive to these medications than others and show acute effects even at low doses.

“You don’t want them to be overwhelmed by this without having supervision nearby,” she said.

The recent surge in ketamine trafficking in Europe also raises concerns about the at-home abuse potential.

“There’s been a consensus in the field that ketamine should not be a take-home medicine; patients can easily develop tolerance, and it is a substance of abuse,” said Mikael Tiger, MD, PhD, associate professor in the Department of Clinical Neuroscience at Karolinska Institutet in Solna, Sweden.

“What we are worried will happen is people increase the dose because they develop tolerance or have a bad day and take an extra pill. If you start doing that, you can quickly develop tolerance; then you enter this vicious circle where you have to escalate,” said Tiger.

He noted that people who abuse ketamine have an increased risk for cognitive impairment, as well as urinary bladder damage.

However, Doebler said that KET01 abuse is unlikely.

“If you grind the tablet, it becomes a mass that cannot go through the nose; instead, you’d have to put it through something like a coffee mill and conduct the extraction with hot water. It takes time, and the ketamine levels that result are not great enough to obtain the high that people seek,” said Doebler, when asked about KET01 abuse potential.

Is the EU ready for a take-home, extended-release ketamine option?

“From the perspective of real-world experience, I think this is a really good development,” said Stewart. “People are suffering. We need better treatments, a variety of different options.”

“The right thing for one person isn’t necessarily the right thing for another person,” he said. “I don’t think it will replace the current treatment we have, but it will be a good addition to it,” he said.

Doebler reported being the chief business officer of HMNC Brain Health. Stewart reported being the medical director of Axonklinikken. Veraart and Tiger reported having no relevant financial relationships.

Liz Scherer is a US-based health/medical journalist with a keen interest in psychedelics and cannabinoid therapeutics. She frequently reports on Canadian and EU health news.