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Experts go from head to toe about the Esketamine Depression Study



SAN FRANCISCO – The ongoing debate over the risks and benefits of the recently approved nasal spray with esketamine ( Spravato Janssen Pharmaceuticals) against treatment-resistant depression (TRD) went into a heated toe area over discussion here at the 2019 Annual Meeting American Psychiatric Association (APA).



Michael E. Thase, MD

In March, the US Food and Drug Administration (FDA) approved the drug in large part on the basis of a pivotal Phase 3 study. The study results presented at last year's APA meeting were published online today in the American Journal of Psychiatry (19459003) (19459003 AJP) along with an accompanying editorial. The study was also the subject of a press conference at this year's meeting.

Investigator Michael E. Thase, a professor of psychiatry at the University of Pennsylvania's Perelman School of Medicine, explained to participants that the drug was not only effective but also fast-acting, with some improvement within the first 24 hours.

Alan F. Schatzberg, MD, Faculty of Medicine, Stanford University, California, then held a presentation based on his companion editorial and noted that the data is somewhat "disturbing" and these questions remain – especially in regards to Dosage, risk and potential for withdrawal symptoms.



Alan F. Schatzberg, MD

After the two presentations, Medscape Medical News asked if Thase had any answer to Schatzberg's concerns, which sparked an extensive, sometimes heated debate between the two physicians.

Thase said he "challenged" some of Schatzberg's points of criticism. [196590] 04] "The fact that you can do something good for a large group of people who have not been helped by other treatments is exciting," said Thase, who is also a member of Corporal Michael J. Crescenz VA Medical's Center ,

"We have to deal with desperate people every day and any attempt to improve their lives should be praised, but this has a background that will have a significant impact," said Schatzberg, noting that despair became one Increased use of drugs with abuse potential leads.

"As a society, we have to make decisions about what constitutes an appropriate risk-benefit ratio," he said.

AJP Editor-in-Chief Ned H. Kalin, Department of Psychiatry, University of Medicine and Public Health Wisconsin, Madison

Although the study results were presented in a poster last year, the magazine not only but also to open discussions on current trends in the field of psychiatry at the forefront of the recent FDA approval and wanted to pair it with the comment. It's not just the paper, but the combination of the two, "said Kalin.

Esketamine is a glutamatergic N methyl D-aspartate receptor antagonist.

In Phase 3 Study More than 200 adult patients with TRD were enrolled at 39 sites in five countries and were randomly given a newly initiated open oral antidepressant every day for 4 weeks and either esketamine 56 mg and possibly 84 mg titration twice weekly (n = 114) or matching intranasal placebo (n = 109).

The newly introduced antidepressant was either duloxetine, escitalopram, sertraline, or delayed released venlafaxine.

The mean on the Montgomery-Åsberg Depression Rating Scale (MADRS) was 37 , 0 and 37.3, respectively, and follow-up continued for all patients until the 24th week.

The primary outcome of the efficacy was the change in MADRS total Scores from baseline to 28th day. The results showed that the active treatment group had a significantly greater change at this endpoint than the placebo group (adjusted mean difference -4.0 points; 95% confidence interval [CI]: -7.31 to -0.64; P = .02). The effect size from baseline to day 28 was 0.3.

The remission, defined as a total score of 12 or less on the 28th day of MADRS, was achieved by 52.5% of the active treatment group versus 31.0% of the placebo group ( P = 0.001) , A 50% improvement in MADRS from baseline, indicating the response rate, was achieved from 69.3% to 52.0%. Dizziness, dissociation, dysgeusia, nausea and dizziness were the most frequently reported adverse events (AEs) in the esketamine group, ranging from 20.9% to 26.1%. Although a transient increase in blood pressure occurred up to 40 minutes after administration of each dose of esketamine, it usually returned to normal about one and a half hours after administration.

Potential Abuse Concerning

IV-Ketamine has been shown to be effective in refractory depression but has not been approved by the FDA. Ketamine has also been used as a party recreational drug for decades.

The new drug, on the other hand, represents a novel method of administration for ketamine and has attracted considerable attention in the field, as noted by Schatzberg in his accompanying editorial entitled "A Word of Wise On Intranasal Esketamine."

"Rarely has a new antidepressant been expected like intranasal esketamine," he writes.

He notes that the Phase 3 study has shown this to be rapid separation compared to placebo and sustained separation on repeated dosing up to 28 days. During the FDA approval process, which included data from this study, "a number of worrying findings were uncovered that should give potential users a break and demand a precise framework for evaluating the benefit-risk balance for using this ketamine formulation." Schatzberg writes in his editorial.

He notes that the small effect size of 0.3 was in the mild range "and there was no further benefit over the initial separation addition." In addition, the "known abuse of ketamine in humans" gives cause for concern, as well like a potential suicide risk.

Three suicides were reported in the Esketamine group. Schatzberg.

Data from a drug spill prevention / termination study mentioned in the FDA's documentation also showed a rapid relapse rate, he added during the press conference.

"We need a better sense of how the drug works," said Schatzberg. "We have not answered many questions about a drug with potential abuse."

Heated Debate

After the presentations, Thase and Schatzberg met with Kalin for a question-and-answer session with the press, which turned into a point-point contrapuntal debate between the two physicians.

Thase noted that both men are of the opinion that esketamine is known as a controlled substance. He added that in a long-term study, investigators did not see patients being diverted and switched to black market ketamine and we did not see any examples of people using other medicines to enhance or even track the effect ", he said.

"Our patients did not behave like drug seekers, behaving like depressive people who responded to treatment," Thase said. "That does not mean that other people do not have problems with ketamine, they do."

He noted that in some countries it is an important drug of abuse and that it can be a recreational drug in the United States drug that some people have serious problems with. "So I totally agree that we have to be careful and reasonable and careful," he said.

"My own opinion is that the endogenous opioid system is part of what makes life worth living, we have it for it." Reasons for this are the ability to enjoy, to consume, to have fun, to pursue and so on. It works in balance with the other neurotransmitter systems and our placebo reactions, which are partially mitigated by the opioid system, "Thase said.

" At the receptor level, the drug is not an opiate. It's just not an opiate. But I agree that it has a releasing or other effect, which is part of why we have to be careful, "he added.

Small effect size

Thase noted that Schatzberg missed the 0.3- Effect size was not impressed, "this is the most significant improvement we have seen in 20 years. At the end of the day, if you look at the last five, six, seven treatments that came out, they were approved with 2 to 3 points difference after 8 weeks and th. The effects occurred more slowly.

"I wish the effect was bigger, but it's bigger than any other recently approved antidepressant," he added.

"The effect is definitely mild," countered Schatzberg. However, he noted that the number of patients to be treated was very low at around 5, "which is good and very encouraging".

Thase added that he also "challenged" Schatzberg's point that the difference between 2 and 4 weeks in relapse was important. "In all our efficacy trials, relapse occurs abruptly, and quite quickly." Whether the relapse occurs after 2 weeks or after 4 weeks is relatively insignificant, he added.

He noted that the relapse curves in his study for the prevention of relapses, the results of which had not yet been published, in every respect resembled the relapse curves in the STAR-D study, "those in the treatment chronic depression, often relapse ".

"Michael raises some interesting points," said Schatzberg. First, blood levels achieved with esketamine are lower than those observed with the intravenous form of the drug.

"Esketamine does not achieve the same levels of blood, but not so." Probably the effectiveness is very high, which is good and bad, "said Schatzberg." If the drug actually mobilizes the opioid system, bless God and that can to be a very good thing. We may have found a way to safely mobilize the opioid system.

"However, over time, data on multiple deaths and multiple suicides are deteriorating regardless of the exact explanation and are somewhat of a concern, and I think more caution is needed than less," he added.

Schatzberg found that patients came in every day and asked if his center offered intranasal ketamine or intranasal ketamine to be thoughtful, which we will recommend to patients. We will get the data, but this data will take a while, "he said.

The REMS program" will help us get that data, "Thase said. This is my life's work and I argue for more careful and longer study with a novel treatment with some problems here is the most reasonable approach.

Careful and Careful Research

Kalin found that many TRD patients have "a level of desperation that exists," as well as putting a lot of pressure on the clinicians who care about it

"Our concern and what you hear is not necessarily that the scientific approach will not be there in the course of time, but when all the excitement, the whole demand, the whole desperation and the whole pressure [decreases] there is a potential to use this in a way that is not necessarily in the best interest of the patients, as we now understand it, "he said 19659014]" My motivation is to make sure we are so careful and be as careful as possible; At the same time, Schatzberg said it was positive and optimistic to investigate and adequately provide it to our patients, "added Kalin

including MDMA, psilocybin and even very low doses of opioids such as buprenorphine.

" How the field reacts to it and how the public and regulators respond to it will be a place of open discussion. People need to be educated about the risks and benefits, and we need to learn more, "he said.

Esketamine is the first of possible options on the horizon, Schatzberg added. People need to understand [this drug] is not crazy, but carries a certain risk. In the end, we try to help the patient, but we also try to bring people to safety.

Hugging

When Thase asked if "It's not crazy" the take-home embassy was laughing at men.

Remarkably, they also ended the session with a hug.

Thase said, however Medscape Medical News after that his takeaway message for doctors reads: "This is a treatment that is really 'in patients who have failed other antidepressants'.

Thase said he was "cautiously optimistic" 8 years ago before investigators began researching the drug.

"I've softened optimism now," he said. If you know what to worry about, you can be reassured that our patients are not seeking drugs and have no problems like addicts. This delivery system prevents this. "

He added that REMS-administered esketamine is being used, he is not worried about the concerns expressed during the debate." For intravenous ketamine d Outside the purview of the FDA and formal follow-up, you might be on some concerns bump. "

However, he believes that esketamine is" really the story of the decade in depression therapy and perhaps in psychotherapy, "Thase said.

No" Silver Bullet "



Ned H. Kalin, MD

In an "Editor's Note," published next month in the AJP, Kalin writes that "despite our best efforts," many psychiatric patients continue to suffer. "We simply need new treatments," he adds.

He said Medscape Medical News that his recommendation for clinicians is, "We should continue and that it is an improved treatment that seems to help some patients quite dramatically. That said, Kalin noted that it's important to be cautious, especially in terms of some of the side effects and abuse potentials, and perhaps the disruptions. "

" We want to be careful, but we don't want to belittle that this is an advance and an opportunity for clinicians and patients.

He added that it is important to remember that this is not a "miracle cure" treatment.

"It's a new bullet and it works differently than our other medications. On the other hand, we have referred to the ketamine clinics where ketamine is used off-label and without regulation. That's why we have to be very thoughtful and careful. Kalin said.

A statement by Janssen at Medscape Medical News stated after the APA press conference that "healthcare providers had limited options for adult patients with treatment-resistant depression" before the FDA recently made their intranasal Spray approved.

Part of the Phase 3 clinical trial involving more than 1700 patients strengthens the drug's robust efficacy and safety profile and significantly improves the symptoms of depression that Spravato may offer to adults with TRD.

The study was funded by Janssen Pharmaceuticals, Thase reported as a consultant or independent contractor for Acadia, Akili, Alkermes, Allergan (Forest, Naurex), AstraZeneca, Axsome, Cerecor, Eli Lilly, Fabre-Kramer, the Gerson Lehrman Group, Guidepoint Global, Lundbeck, Johnson & Johnson, MedAvante, Merck, Moksha8, Nestlé (Pamlab), Neuralstem, No vartis, Otsuka, Pfizer, County, Sage, Sunovion and Takeda; Received a scholarship or research grant from Acadia, the Agency for Health Research and Quality, Alkermes, Allergan (Forest), AssureRx Health, Avanir, Axsome, Intracellular, Janssen Pharmaceuticals, Johnson & Johnson (including for the present study), NIMH, Otsuka , the Institute for Patient-Centered Outcomes and Takeda; and royalties from the American Psychiatric Foundation, Guilford Publications, Herald House, and W.W. Norton & Company. In addition, his spouse is employed by Peloton Advantage, which works with a number of pharmaceutical companies. The data for the other authors of the study are listed in full in the original article. Schatzberg announced that it had received support from Janssen; Consultant to Alkermes, Avanir, Brain Resources, Bracket, Compass, Delpor, Epiodyne, GLG, Jazz, Janssen Pharmaceuticals, Lundbeck / Takeda, McKinsey and Company, Merck, Myriad genetics, Neuronetics, Owl analytics, Pfizer, Sage, Sunovion and Xhale; Participation in Corcept (co-founder), Delpor, Dermira, Epiodyne, Gilead, Incyte Genetics, Intersect ENT, Madrigal, Merck, Owl Analytics, Seattle Genetics, Titan and Xhale; and to be listed as the inventor of patents for pharmacogenetics and the use of antiglucocorticoid in predicting the response to antidepressants. Kalin did not announce any relevant financial relationships.

Annual Meeting 2019 of the American Psychiatric Association (APA). Presented on May 20, 2019.

Am J Psychiatry . Published online May 21, 2019. Volltext, Editorial

Follow Deborah Brauser on Twitter: @MedscapeDeb

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