Bait and Switch: the Great Ketamine “Breakthrough”
Post by Johanna Ryan
Maybe you heard the exciting news last month about a game-changing new treatment for depression. It offered new hope to millions who were not helped by existing drugs, the headlines said – the first real breakthrough in depression treatment since Prozac, some thirty years ago.
The product was Janssen’s esketamine nasal inhaler, described as a new variation on an old generic drug. Ketamine is an anesthetic, given by injection (IV) for invasive or unpleasant medical procedures that don’t require a complete knock-out. It’s known to cause feelings of “dissociation” (a sense of being outside one’s body or personal identity) and, occasionally, hallucinations. Some people like this effect, which has led to an illicit market in ketamine or “Special K” for recreational users. (Esketamine is simply one of the two forms of the ketamine molecule. It’s not a new drug, exactly, but Janssen can patent it as one, for an obvious economic advantage.)
For at least a decade, both studies and case reports have described severely depressed people getting rapid and robust relief within hours of a ketamine injection. Now Janssen (a subsidiary of Johnson & Johnson) claimed to have turned this old and rather scary-sounding drug into a new, safe and effective treatment which it dubbed “Spravato.”
“Is that all there is?”
I had been following the Ketamine Story for several years, and had shared the initial excitement (along with some caution). But when Janssen rolled out its results at an FDA hearing on February 12, I was stunned at how underwhelming they were. Is that all there is, I wondered?
In order to approve a new drug, the FDA generally requires only two positive studies. Spravato couldn’t even meet this test – only one four-week study had shown it to be more effective than placebo. And those “positive” result seemed awfully weak. Patients who snorted esketamine twice a week for four weeks showed about a 20-point reduction in scores on a depression rating scale – but those taking hits off a placebo inhaler had scored a 16-point decline! The difference was “statistically significant,” but just barely. Worse yet, it made the placebo look pretty darn good:
The other three studies of Spravato’s effectiveness were judged “negative.” So the FDA allowed Janssen to use a “withdrawal” study – in which people who did report feeling better on the drug were either allowed to continue, or switched to placebo – as its second “positive” study. Because such studies tend to be slanted in favor of the test drug, this is usually prohibited. But for such a promising product, with such exciting potential, an exception could be made, FDA officials said.
Wait a minute. What excitement? I couldn’t see it. Apparently, however, the FDA’s advisory panel could. They did insist that Spravato be used under medical supervision, to assuage worries that it could be abused. (Oddly, no one seemed to have asked the patients if they found themselves itching for another “hit.”) Then, by a margin of 14-2 with one abstention, they voted for approval. Of the two no votes, one came from the consumer representative, Kim Witczak.
A Double Bait-And-Switch
As a patient, I wish the panel had called a time-out instead. The Spravato story, it seemed to me, was a bait-and-switch on two levels:
- The buzz around this drug had been based on impressive results from IV ketamine treatment: one or two full-dose infusions, with no attempt to suppress the dissociative or “trip-inducing” effects. But “esketamine inhaler therapy” was a different animal altogether: a lower dose designed to minimize these effects, and thus be suitable for long-term use. The results had been remarkably UN-impressive. Meanwhile, the hazards of using esketamine on a “maintenance” basis were unknown. They might be completely different from those associated with one or two full-on “trips.” There were at least three suicides in Janssen’s inhaler studies – all in the treatment group.
- The second bait-and-switch: “Severe depression” with an imminent risk of suicide was cited as the condition for which this drug was so urgently needed. And IV ketamine did seem to work rapidly for such patients. But those were not the patients chosen to test Janssen’s inhaler: subjects with any suicidal ideation or behavior in the past six months were excluded! Instead, the target was patients with treatment-resistant depression or “TRD,” defined as those who had tried at least two antidepressant pills without adequate relief.
That is not to trivialize TRD – most people carrying that diagnosis are definitely suffering. But the majority are not at imminent risk of suicide or otherwise in acute crisis. More commonly they are trapped in a chronic state of low energy, low motivation and “anhedonia” or inability to feel pleasure, which can drag on for years.
I know, because I’m one of them – and I almost enrolled in a Spravato study. Here’s what I learned from the experience.
Could we try something different?
By the time those “ketamine breakthrough” stories hit the news in 2013, I was fed up with drug treatments for depression. Like many with “TRD,” I had tried perhaps a dozen antidepressants over the years. A few had helped for awhile, then lost their effect; most had not helped at all. Even when I felt no better on the drugs, quitting them led to worse distress. I was beginning to think my problem was not my terrible treatment-resistant condition, but the treatments themselves. If I did have a “chemical imbalance,” could it be a product of my years of maintenance drugging?
If ketamine treatment interested me at all, it was mainly because it sounded different from all those previous “breakthroughs.”
First of all, it was not a maintenance drug to take for months or years. It was more like a one-shot intervention that might interrupt the cycle of depression, if only temporarily – much like ECT did for some people, but perhaps in a safer and less disruptive way.
Better yet, it might be up to me to find a meaning or context for that temporary boost, and make it count. I had heard of cases where a single “trip” on psilocybin or LSD had helped people shed crippling attitudes or behaviors – often with some skilled coaching, but without the need for endless return trips. It had been a long time since I’d heard doctors express any interest in such coaching. It was a long time since I’d heard doctors mention my capacities as an individual, either. Finally, if it didn’t work, I could just set it aside and move on, with no need to face a protracted withdrawal.
The “experts,” however, saw it differently. While most new drug treatments made them swoon with excitement, they all seemed strangely wary this time. What was needed, they agreed, was not ketamine, but a new drug that had similar qualities but did not cause dissociation – “ketamine without the trip,” as one researcher put it. And above all, it would have to be suitable for long-term maintenance use.
As reports of a “ketamine miracle” spread, private clinics sprang up to offer injections on a cash-only basis. The “experts” expressed alarm at the flimsy evidence base for such treatments – but were not about to fill the research gap themselves.
Instead, in November 2013, the FDA awarded “breakthrough status” to Janssen’s proposed intranasal esketamine inhaler, to facilitate getting it to market as fast as possible. (To justify this gift to Janssen, ironically, FDA officials cited the dramatic success of an earlier study featuring … a single IV ketamine injection.)
Coming soon to a clinic near you …
A little over three years later, esketamine research came to my hometown, and I was urged to apply. The “breakthrough” was almost ready for prime time! I reported to the study center to fill out questionnaires and hear the details.
Not only was this “ketamine without the trip”, I discovered – it was definitely a maintenance drug. The first phase would run for four weeks, and if the drug seemed to work I would enroll in a continuation study for an entire year! Worse yet (from my point of view) it would function as an add-on to the same antidepressants I’d tried without success for years. Each subject, having “failed” two antidepressants already, would be placed on a third pill to be selected by the study doctor. You might get a real esketamine inhaler or a placebo one, but you would definitely get a live antidepressant.
The first stumbling block was that most of my drug treatment “failures” were years in the past; only one had occurred in my “current depressive episode.” No problem, said the study doc: they could simply re-calculate the boundaries of my “current episode!” Granted, those boundaries were pretty arbitrary; like many citizens of TRD Nation, my life often felt like one long, dreary “episode.” Still, the approach seemed a bit loose.
A larger stumbling block was that “new antidepressant.” The choices included two SSRI’s (escitalopram or sertraline) and two SNRI’s (duloxetine or venlafaxine). I had tried them all in the past, with results that ranged from lackluster to disastrous. Well, said the study doc, we could still pick the one that had given me the fewest nasty side effects! The final stumbling block: if I were still taking that most recent “failed antidepressant,” I would have to withdraw from it in a four-week taper. That, I knew from experience, spelled trouble.
I told the clinic staff I didn’t think I could participate. They seemed sorry to lose me. A study starting soon would combine esketamine with a brand-new antipsychotic called brexpiprazole, they said. Would I like to try that? Dear god, no. I would carry on without that inhaler for the time being. Eight months I learned that “my study”, dubbed TRANSFORM-1, had been a bust. It was one of the three “negative” studies, although Janssen’s press release tried its best to spin the results. I wasn’t too surprised.
A “breakthrough” for the bottom line?
Since then, I’ve come to think that the only real “breakthrough” in the esketamine studies was a financial one for Janssen. There’s no profit in a cheap drug like ketamine that’s been off-patent for decades—and damn little profit in a drug meant for one-time or emergency use. But esketamine, a tweaked version encased in a patented delivery device, could fetch a nice price. Especially if it were packaged as a maintenance drug to take for months or years.
The scariest thing possible in a new-drug trial, I’ve heard some cynics say, is that people start dying – but the second scariest thing is that people start getting better. Where’s your revenue stream then? Spravato may do little or nothing for depressed people who have tried other treatments without success. But as a guarantor of future profits, it may be just the “game changer” the drug companies have been yearning for.
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Ineffective at best. Deadly at worst. Disgusting as usual.
“Hope has never been higher in the medical community …
Chin-Chin
https://www.chinatimes.com/realtimenews/20190306001404-260408
2019年03月06日 09:50
I didn’t suffer from depression until I was falsely diagnosed with bipolar 1 and aggressively drugged for 11 years….causing drug-induced depression (& many other ‘symptoms’=side-effects). I’m ‘officially’ free of all diagnosis today (paperwork!), my exit ‘gift-tag’ being ‘unpecified’ anxiety, F41.9……no f*cking kidding.
Having said that….depression is becoming the ‘new’ (recycled) marketing target for the industry machine. Bipolar is still a ‘darling’ of the industry, but folks are beginning to notice it’s massive lack of credible diagnostic code application, regardless of it’s infinite expansion of ‘symptoms’.
Depression never went away, just distracted by ALL the other newly manufactured disorder-codes & vague treatments whose results are skewed, creatively edited, & tailored to fit the ‘new approach’ to old complaints.
The FDA has a poor track record standing for integrity regarding trials & results dealing with Pharma (“follow the …”, well, u know), this is no different, but the marketing should be a ‘slam-dunk’, familiarity in name-recognition translating to an illogical but easier acceptance by consumers.
Scary, indefensible, dangerous to trusting sufferers; venality never stopped them before & won’t with esketamine….& all the ‘knock-offs’ to follow. And NO, it will never ‘cure’, there will be NO ‘recovery’; just “lifelong” ‘maintenance….the treatment-paradigm that is the industry’s definition of a ‘successful’ drug. Deaths while ‘on’ the drug will be spun to create ‘urgency’ for the ‘new epidemic’ of depression & suicide=more sales. The bipolar “gold-rush” model rides again. The “pediatric-depression” faux-emergency is coming to media any second now…
We’ve seen this movie.
Janssen knows it’s way around bullsh*t claims of efficacy & imaginary safety regarding psych drugs. They’re extremely comfortable & polished with this hustle.
Have some Topamax while you’re waiting for your Spravato.
‘Oh my goodness gracious!’
Now, they are enticing people by putting this stuff into a funky rocket missile type contraption.
One instant shot and you will be as good as gold. All your troubles will be blasted away!
It is safe and effective just like the other notorious claims of well known brands.
I am always sceptical when they claim that something is safe and effective.
There is always an element of risk and doubt when I hear/read the word safe and effective.
If meds are safe and effective, people like myself would not be here on RXISK , retelling our tragic stories.
Sadly, we are paying a very high price for speaking up and it saddens me that we are told that we live in a country of democracy when the powers of corruption impact every aspect of our lives.
It is Very funky! Looks similar to the cool looking vapes marketed to people who wanted to give up fags.Maybe they could make a few different choices of design to attract more users – photos of a few celebs who have ‘come out’ about their depression and these funky little pocket rockets can be on the street in no time. heroin and other stuff gets easily shoved up the nose so Johnson and Johnson have learned a good trick there.
On China Time (Annie’s link above) – only certified prescribers can get this drug..! When it’s being promoted like a magic fix they know that’s not likely – there;ll be dealers cooking it up already. ‘It functions differently to other anti depressants and can ease symptoms in 1 day!! Strewth imagine a trip on that! Another selling point is that this is a drug targeted especially for people suffering long term depression and who often turn to suicide. Good to know they care. China Times (which has just bigged up the rocket propelled drug- Zhongshi Newsletter Cares About You. Protect Yourself and Stay Away from Drugs’.
I fail to see the attraction of this “medication”.
In the first instance, those already hurt by, or struggling on, the usual drugs are not going to touch this one with a barge pole are they? Surely, it’s a case of ‘once bitten, twice shy’.
On the other hand, those who find the usual ADs beneficial (?) are not going to be tempted away from them are they? Their mantra being “these have saved my life” surely means they would be idiotic to change prescription.
So, at who exactly do the manufacturers aim this new drug? It’s my guess that it’s aimed at youngsters, new to the need for a prescribed drug, who may well find a ‘squirt up the nose’ more acceptable than taking a boring, old-fashioned tablet any day of the week!
Boom-Berg
https://www.bloomberg.com/opinion/articles/2019-03-06/j-j-ketamine-like-spravato-depression-drug-isn-t-a-surefire-hit
Skeptical Steve
https://www.bing.com/videos/search?q=spravato&&view=detail&mid=37C60E9BA3B018DEB21B37C60E9BA3B018DEB21B&&FORM=VRDGAR
https://www.spravato.com/
‘Brutal disaster.’ Allergan’s would-be antidepressant fails patients in four studies
https://www.statnews.com/2019/03/06/brutal-disaster-allergans-would-be-antidepressant-fails-patients-in-four-studies/?utm_source=STAT+Newsletters&utm_campaign=f3bd68afa0-Pharmalot&utm_medium=email&utm_term=0_8cab1d7961-f3bd68afa0-149674737
Thanks for this article. Should have guessed.
Ketamine-like drug for depression could get UK licence within the year
Esketamine could initially become available through private clinics but potential side effects raise concerns
https://www.theguardian.com/science/2019/jul/12/ketamine-like-drug-for-depression-could-get-uk-licence-within-the-year
Hannah Devlin Science correspondent
Fri 12 Jul 2019 17.04 BST
“We haven’t had anything really new for 50 or 60 years. What’s particularly exciting is the arrival of a new type of treatment and that’s ketamine,” he said. “It’s got a different pharmacology. It’s not just the same old steam engine, it seems to work in a different way and it seems to work more quickly.”
“The cost of esketamine is dramatically high and comes with a very large and scary side-effect profile,” he said. “It is so potentially dangerous that clinicians are required to sit with patients for two hours after they are administered the drug. There is no other antidepressant that I know of that requires one hundredth of that kind of observation after administration. The upshot is that the drug is an over-hyped ripoff.”
FDA Overlooked Red Flags In Drugmaker’s Testing of New Depression Medicine
https://khn.org/news/fdas-approval-of-new-depression-drug-overlooked-red-flags-in-its-testing/
The problem, critics say, is that the drug’s manufacturer, Janssen, provided the FDA at best modest evidence it worked and then only in limited trials. It presented no information about the safety of Spravato for long-term use beyond 60 weeks. And three patients who received the drug died by suicide during clinical trials, compared with none in the control group, raising red flags Janssen and the FDA dismissed.
The FDA, under political pressure to rapidly greenlight drugs that treat life-threatening conditions, approved it anyway.
James Moore Retweeted
Dr. Terry Lynch @DrTerryLynch 10h
@CEP_UK @dropthedisorder @PaulMinotMD @leoniefen @barneyhound @Mad_In_America @jf_moore @HengartnerMP @ClinpsychLucy @joannamoncrieff @alyne_duthie @truthman30 @balfe_robert @jill_d35 @galavpsychology @DrAlecGrant @nhunterpsych @MITUKteam @ReadReadj @recover2renew @benzosarebad
https://doctorterrylynch.com/the-media—and-the-public—must-apply-a-critical-approach-to-mental-health-information/
James Moore @jf_moore
“There’s grounds to think this drug can be useful,” says David Healy, professor of psychiatry at Bangor University. “But the version that has been brought to market is probably going to do more harm than good.”
Has esketamine been vastly overhyped?
By William Ralston
20 July 2019
The first new antidepressant since Prozac is… ketamine. OK, not quite. There is no patent on the infamous party drug, but big pharma is now marketing a derivative with worryingly unclear outcomes
https://www.gq-magazine.co.uk/lifestyle/article/esketamine-antidepressant
Esketamine is a drug that divides opinion, but one certainty is that it’s been vastly overhyped. Another is that nobody really knows what the long-term effects of esketamine consumption are and there are concerns about the drug’s withdrawal effects after three of the study’s participants committed suicide within 20 days of its end, despite continuing on traditional antidepressants.
The FDA report said “it is difficult to consider these deaths as drug-related”, due to the small number of cases and the severity of the patients’ underlying illness, and Janssen said data from the trials did not suggest that esketamine is associated with increased risk of suicidal ideation or behaviour. Nevertheless, by rushing these drugs to market without clear evidence as to their safety and efficacy, we risk disappointment and suffering for those who need them most.
Worrying trend, towards ‘treatment-resistant depression’ drug approval
Sage Therapeutics to pursue high-risk, high-reward plan for experimental depression pill
By Adam Feuerstein @adamfeuerstein
July 24, 2019
https://www.statnews.com/2019/07/24/sage-therapeutics-to-pursue-high-risk-high-reward-plan-for-experimental-depression-pill/?
Sage Therapeutics is advancing its experimental pill SAGE-217 into a pivotal clinical trial for people with treatment-resistant depression, the company said Wednesday.
Treatment-resistant depression will be the third proposed indication for SAGE-217, a once-daily oral medicine that has already established efficacy in postpartum depression and is being investigated in an ongoing Phase 3 study of major depressive disorder. The Cambridge, Mass.-based company intends to start a Phase 3 study in treatment-resistant depression before the end of the year, said CEO Jeff Jonas said in an interview.
James Moore @jf_moore 22h
New buzzword to look out for ‘neurosteroids’ New antidepressants on horizon – http://ScienceBlog.com
New antidepressants on horizon
October 29, 2019
https://scienceblog.com/511637/new-antidepressants-on-horizon/
For example, when I saw the data for the postpartum drug brexanalone, I would point out that the aim wasn’t only to treat postpartum depression but that neurosteroids potentially had broader uses. Those included clinical depression in men and women, anxiety and treatment-resistant depression. And as early data first came in on the latest drug, SAGE-217, it became clear that it could be effective in men and women with depression and that we probably should study it further in patients with treatment-resistant depression. That’s our plan here at the Taylor Family Institute: to evaluate neurosteroids in patients whose depression has not been relieved by other drugs because that’s where we could see the greatest impact.
recovery&renewal @recover2renew 1h
recovery&renewal Retweeted The BMJ
OMG …
The BMJ @bmj_latest
So far the evidence suggests that patients stand to benefit from ketamine-related drugs. We need a strong monitoring system—which must include ketamine as well as esketamine” @rcpsych
Rupert McShane: A drug not a miracle—why we need a new system for monitoring ketamine
July 26, 2019
https://blogs.bmj.com/bmj/2019/07/26/rupert-mcshane-a-drug-not-a-miracle-why-we-need-a-new-system-for-monitoring-ketamine/
The European Medicines Agency and the UK drugs regulator will make a decision in November on licensing esketamine—if approved it would become available through private clinics. And early next year, the National Institute for Health and Care Excellence is scheduled to decide on whether to approve it for NHS use.
The MHRA, NICE, NHSE, DHSC, pharma, Royal Colleges, NHS and private providers need to thrash out how this could work. The problem doesn’t clearly lie with any one agency. But if we ignore ketamine because its use is off-label, or ‘out of scope’, or because there isn’t a precedent for multi-drug monitoring, or because it’s difficult to see how to fund it, we risk descent into overuse, backlash and stigma.
So far the evidence suggests that patients stand to benefit from ketamine-related drugs. We need wide access with strong monitoring—which must include ketamine as well as esketamine—to ensure that this is not just a flash in the pan.
Trump Orders VA to Buy “a Lot of” Esketamine for Veterans
https://www.madinamerica.com/2019/08/trump-orders-va-buy-lot-esketamine-veterans/
‘This is a form of a stimulant where, if someone is really in trouble from the standpoint of suicide, it can do something,’ Trump said. ‘It’s pretty well known, it just came out. We have calls in to Johnson & Johnson now, we’ve been talking to them for two months on buying a lot of it.’”
Revealed: Doctors pushing new drugs don’t have to admit they are funded by the pill’s makers … and a treatment for depression using Class B drug ketamine is just the latest example
More than four in ten British health professionals who take money from drug companies don’t disclose those payments or say where the money came from
There is no requirement that they do so as all disclosure is voluntary in the UK
One example being pushed by doctors is use of ketamine to treat depression
By John Naish
Published: 23:06, 26 August 2019 | Updated: 23:14, 26 August 2019
https://www.dailymail.co.uk/health/article-7396961/Doctors-pushing-new-drugs-dont-admit-funded-pills-makers.html
Recently, leading depression experts lined up at a London briefing to explain how an engineered version of the drug, called esketamine, promises a breakthrough in providing fast-acting help to sufferers of treatment-resistant depression.
What was not made clear in reports of the briefing is that Professor Young, Dr McShane and Dr Zarate have conflicts of interest that could potentially compromise their independence as advocates of ketamine and esketamine.
EMA Panel Backs Esketamine Nasal Spray for Resistant Depression
Megan Brooks
October 18, 2019
https://www.medscape.com/viewarticle/920058?src=soc_fb_share&fbclid=IwAR2Si1wHQLjSAGBgw9Sz1G-VX348xba2H7Thj6MWld9oFhNrB-VWzXt5TmY
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of esketamine nasal spray (Spravato, Janssen-Cilag) in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) for adults with treatment-resistant major depressive disorder (TRD).
Patients are considered to have TRD if they have not responded to at least two different treatments with antidepressants in the current moderate to severe depressive episode.
A concluding summary of the efficacy and safety of esketamine from the data presented by Janssen to the FDA
https://www.bmj.com/content/366/bmj.l5572/rr-11
Public Health England (PHE) has just published a review of drug classes causing dependence and withdrawal, including opioids, benzodiazepines, z-drugs, gabapentinoids, and antidepressants, concluding that one in four Britons are on these drugs, a widespread issue of concern [4]. When each of these classes of drug were introduced into clinical practice they were said to have ‘safe profiles’, and were approved for use based on short-term studies in the absence of comprehensive long-term safety studies. Recognition of the damage these drugs have done to many patients caught in a cycle of dependence and withdrawal effects has taken decades.
https://www.bmj.com/content/366/bmj.l5572
No one will thank the MHRA if they introduce another drug that leads to long-term medical complications and significant problems with dependence and withdrawal, just because it has a ‘novel’ mode of action.
James Moore Retweeted
Mark Horowitz @markhoro 1h
Puncturing the hype about esketamine’s woeful efficacy. A very good summary of @eturnermd1’s recent Lancet Psychiatry article https://bit.ly/32NaFmf . Not to mention the concerning safety issues with this drug, more here: https://bit.ly/2Qk8xiY
FDA’s Rapid Approval of Esketamine for Severe Depression Questioned
Pauline Anderson
November 13, 2019
https://www.medscape.com/viewarticle/921248?src=soc_tw_191116_mscpedt_news_mdscp_esketamine&faf=1
While some experts have hailed intranasal esketamine (Spravato, Janssen) as a “game changer” for treatment-resistant depression (TRD), others are concerned over the US Food and Drug Administration’s (FDA) rapid approval of the drug.
In an editorial published online October 31 in Lancet Psychiatry, Erick H. Turner, MD, who sits on one of the FDA advisory committees that recommended approval of Spravato, said the drug did not meet standard criteria for FDA approval and that there was little evidence to support its safety and efficacy based on data from three short-term, phase 3 trials and one withdrawal trial.
Turner, who is a psychiatrist at Oregon Health and Science University in Portland, noted that only one of the three trials that led to the drug’s approval was positive.
“Accepting just one short-term trial as being enough is an historic break from precedent,” Turner told Medscape Medical News.
“Based on the evidence provided in Janssen’s application, the FDA should not have approved the drug,” Spielmans, who researches antidepressant medications, told Medscape Medical News.
Why a spray almost identical to ‘party’ drug ketamine is set to be approved to ‘treat’ depression
Esketamine is set to be approved as a wonder cure for people with depression
This prompted protests from experts who say the tests on it were inadequate
The drug ketamine is legally used as a horse tranquilliser and an anaesthetic
By John Naish for the Daily Mail
Published: 01:13, 19 November 2019 | Updated: 01:15, 19 November 2019
https://www.dailymail.co.uk/health/article-7699191/Why-spray-identical-party-drug-ketamine-set-approved-treat-depression.html
This has prompted protests from experts who argue that the tests on esketamine have been inadequate and that even in those tests, involving some 1,600 people, esketamine was associated with six deaths.
Last month, a European Union regulator unexpectedly recommended approval for esketamine to be used as a depression drug across the EU.
The news prompted warnings by leading experts and scathing attacks in the medical journal The Lancet.
In September, Public Health England published a landmark report warning of the addictiveness of prescribed drugs for depression and other common psychiatric problems.
MPs on the All-Party Parliamentary Group (APPG) for Prescribed Drug Dependence believed that UK approval for the drug was to be discussed this month by the drug-safety watchdog, the Medicines and Healthcare products Regulatory Agency.
The APPG repeatedly wrote to the agency asking about this meeting, so it could present its objections, but heard nothing.
Instead, last month, the APPG learned that Janssen had sent an application for European-wide approval to the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, the EU regulator, and that this has now been granted provisional approval.
However, in March, esketamine was approved for use by the Food and Drug Administration (FDA) in the U.S. in patients with treatment-resistant depression, sparking fears it may subsequently be approved in the UK.
Head of neuroscience at Janssen, Dr Husseini Manji, said they are pleased with CHMP’s recommendation: ‘For decades there have been no new treatment options for patients with treatment-resistant depression. Esketamine represents a new way to manage this.’
Ketamine-like drug for depression gets UK licence
Psychiatrists divided on ‘game-changing’ esketamine due to potential for addiction
https://www.theguardian.com/science/2019/dec/19/ketamine-like-drug-depression-uk-licence-esketamine?CMP=share_btn_tw
Hannah Devlin Science correspondent
@hannahdev
Thu 19 Dec 2019 18.02 GMT
John Read, a professor of clinical psychology at the University of East London, who was among the critics, said: “The fear is that in a few years we will be having a Public Health England review into people who can’t get off esketamine. At this stage we really should be cautious.”
According to Young, esketamine is the first of a wave of new drugs in the pipeline for depression, including the psycho-active drug psylocibin, found in magic mushrooms, which is currently the subject of trials.
“We’re seeing lots of work with new chemical entities that are very different from old SSRIs,” he said. “Hopefully this will be the harbinger of a new era for treatments.”
John Read
@ReadReadj
THE DISTURBING CASE OF THE STREET DRUG KETAMINE Are Our Regulatory Bodies Prioritising Drug Company Interests Over Public Safety?
https://www.madintheuk.com/2019/12/regulatory-bodies-prioritising-drug-company-interests-over-public-safety/
The UK’s Medicines & Healthcare Products Regulatory Agency [MHRA] is refusing to respond to the concerns of psychiatrists, parliamentarians, patients and other experts about the impending licensing of the street drug ketamine as a treatment for depression.
In March this year, the USA’s Food and Drug Administration approved Spravato (esketamine), on the basis of just one efficacy study.
Mark Horowitz
@markhoro
Another examination of Janssen’s FDA application for esketamine finds the drug to be ineffective as an antidepressant, and associated with a host of worrying side effects.
Esketamine for treatment resistant depression: a trick of smoke and mirrors?
https://www.cambridge.org/core/journals/epidemiology-and-psychiatric-sciences/article/esketamine-for-treatment-resistant-depression-a-trick-of-smoke-and-mirrors/F8BB2D5C3F290FE671639CBB0F31C7E9
Finally, we argue that the EMA should take into due account all these critical issues when assessing the marketing authorisation of esketamine for Europe, and, more broadly, we call for a radical change of current regulatory rules for psychotropic drug approval.
Trump touted a new antidepressant as a solution for veterans. Only 15 have been treated
By Megan Thielking @meggophone
January 6, 2020
https://www.statnews.com/2020/01/06/only-15-vets-treated-esketamine/?utm_source=STAT+Newsletters&utm_campaign=f2fc7721ab-Pharmalot&utm_medium=email&utm_term=0_8cab1d7961-f2fc7721ab-149674737
In August, President Trump proudly proclaimed that he had directed the Department of Veterans Affairs to buy “a lot” of a drug known as esketamine, the first new major depression treatment with a novel mechanism to hit the U.S. market in decades.
“Its results are incredible,” Trump said at a veterans convention in Kentucky. “I’ve instructed the top officials to go out and get as much of it as you can.”
As of mid-December, the VA had treated just 15 veterans across the country with the drug. The nasal spray, which was developed by Janssen and named Spravato, was only available at seven of the agency’s facilities — out of more than 1,200.
The VA treated its first patient with Spravato in June.
“[The studies] are not robust. They’re not strong results. You pull one thread and the whole thing unravels,” said Turner.
https://www.bmj.com/content/366/bmj.l5572
1. Correspondence to: S Jauhar Sameer.jauhar@kcl.ac.uk
We should cautiously welcome this new therapeutic option
On 5 March 2019 the US Food and Drug Administration approved esketamine nasal spray in conjunction with an oral antidepressant for people with treatment resistant depression.
2. Esketamine for treatment resistant depression is not recommended by NICE
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m329 (Published 28 January 2020)
Esketamine for treatment resistant depression
An esketamine nasal spray may not be made available on the NHS for patients with treatment resistant depression because of uncertainties over its clinical and cost effectiveness, says draft guidance from the National Institute for Health and Care Excellence.1
NHS watchdog rejects use of party drug ketamine as antidepressant despite hype over treatment
Officials say there is not enough evidence ketamine works long-term
NICE also said the £10,000 course price is too high for the NHS to fund
The drug delivered via nasal spray is chemically similar to the party-drug version
https://www.dailymail.co.uk/health/article-7934897/NHS-watchdog-rejects-use-party-drug-ketamine-antidepressant-despite-hype-treatment.html
By Ben Spencer Medical Correspondent For The Daily Mail
Published: 00:01, 28 January 2020 | Updated: 00:11, 28 January 2020
A radical depression treatment derived from party drug ketamine is set to be rejected for use on the NHS.
There has been months of hype over the treatment – the first antidepressant with a new mechanism of action to be licensed in 30 years.
But NICE say there is not enough evidence it works long-term, and the price – which exceeds £10,000 for the average course – is too high for the NHS to fund.
‘Many psychiatrists have been concerned at the lack of evidence that esketamine is really a helpful treatment for depression.
‘There are also unanswered questions about the extent to which it might cause unwanted effects and how it could be safely used in practice.
John Read – UK Esketamine Approval – Not so Fast
https://www.madinamerica.com/2020/02/john-read-esketamine-approval/
By
James Moore
February 1, 2020
John joins us to discuss the UK licensing of esketamine nasal spray (Spravato) for so-called ‘Treatment Resistant Depression’. John led a group of 12 academics and professionals who wrote to the UK regulator expressing concerns about esketamine.
How there was no response from the MHRA to the concerns raised by John’s group.
In addition, no reply was made to concerns raised by Sir Oliver Letwin writing on behalf of the All Party Parliamentary Group on Prescribed Drug Dependence as well as letters from independent researchers from Kings College London and a group of service users.
A recent response to the approval by the UK National Institute for Health and Care Excellence.
A response to the NICE announcement from the Science Media Centre.
Lawmakers Investigating Whether Trump Pals Had Stake in Risky Drug He Pushed for Veterans
https://www.madinamerica.com/2020/03/around-web-lawmakers-investigating-trump-pals-stake-risky-drug-veterans/
From ProPublica: “House Democrats are expanding their investigation of outside influence at the U.S. Department of Veterans Affairs, examining whether a push to use a new antidepressant from Johnson & Johnson was advanced by a group of unofficial advisers who convened at Mar-a-Lago, President Donald Trump’s private club.
Inside Trump’s VA
Trump Endorsed a Risky Antidepressant for Veterans. Lawmakers Want to Know if His Mar-a-Lago Pals Had a Stake in the Drugmaker.
https://www.propublica.org/article/donald-trump-veterans-spravato-antidepressant-johnson-and-johnson
House Democrats requested emails and financial records as they investigate why the president told the VA to “corner the market” on a Johnson & Johnson drug.
Esketamine for Depression:
“Repeating Mistakes of the Past”
Researchers argue that trials of esketamine for depression do not demonstrate efficacy and downplay the potential harms.
By
Peter Simons
June 8, 2020
In a new article published in The British Journal of Psychiatry, researchers Joanna Moncrieff and Mark Horowitz reviewed the evidence for the use of esketamine for depression. They found a lack of evidence for efficacy and a minimization of the harms of the drug.
“Esketamine has been licensed for ‘treatment-resistant depression’ in the USA, UK, and Europe. Licensing trials did not establish efficacy: two trials were negative, one showed a statistically significant but clinically uncertain effect, and a flawed discontinuation trial was included, against Food and Drug Administration precedent. Safety signals – deaths, including suicides, and bladder damage – were minimized,” Moncrieff and Horowitz write.
https://www.madinamerica.com/2020/06/esketamine-depression-repeating-mistakes-past/
Finally, Janssen submitted a safety trial to demonstrate that taking esketamine was not dangerous. In all the trials conducted by Janssen, which included about 1800 patients in the esketamine arm, there were six deaths in the esketamine group. Three were suicides, and two of those occurred in people who had no previous suicidal thoughts. All three suicides occurred just after discontinuing the drug, indicating that they could have resulted from withdrawal effects.
Johnson & Johnson antidepressant spray approved for treating those at risk of suicide
BY
CYNTHIA KOONS AND BLOOMBERG
August 3, 2020 3:12 PM GMT+1
https://fortune.com/2020/08/03/johnson-johnson-spray-suicide-treatment/
Johnson & Johnson’s Spravato has been approved as the first antidepressant for actively suicidal people, as doctors are becoming increasingly concerned about COVID-19’s effect on the mental health of Americans.
The Food and Drug Administration approval means the quick-acting nasal spray will be available to people with suicidal thoughts and a plan to put them into action, said Michelle Kramer, vice president of J&J’s U.S. neuroscience medical-affairs unit. That constitutes 11% to 12% of as many as 17 million Americans who have major depressive disorder.
Spravato has been used by about 6,000 people for treatment-resistant depression since its approval in March 2019, Kramer said. J&J’s decision to study it in depressed people actively contemplating suicide bucks a trend among drugmakers who routinely exclude such patients from trials.
John Read
@ReadReadj
When NHS watchdog protects public from Ketamine, an ineffective, expensive, addictive, hallucinogenic street drug, Psychiatry accuses it of discrimination
@CEP_UK@ClinpsychLucy@psychgeist52@Altostrata@JDaviesPh
@joannamoncrieff
https://mol.im/a/11222317 via @MailOnline
NHS spending watchdog rejects ketamine nasal spray for depression as psychiatrists accuse NICE of ‘discrimination’ against mental health patients – after EU approves £1,000-a-week drug
https://www.dailymail.co.uk/health/article-11222317/NHS-rejects-ketamine-depression-psychiatrists-accuse-NICE-mental-health-discrimination.html
A row has broken out between NHS spending watchdogs and top mental health doctors over approval of a controversial ketamine-based antidepressant.
Spravato, a nasal spray also known as esketamine, got the green light from the European Medicines Agency in December 2019 as a fast-acting treatment for depression sufferers who had not responded to at least two other standard medications.
Trials showed that the benefits of the drug, which is taken alongside standard antidepressants, were also long-lasting, and patients who took it were almost half as likely to suffer a relapse within a year as those taking just antidepressants.
But in May, UK prescribing body the National Institute for Health and Care Excellence (NICE) rejected Spravato, which costs up to £489 per dose. Concerns were raised over the fact that the drug had to be administered in hospital, as often as twice a week, in order to monitor patients’ reactions and minimise safety risks.
Esketamine is a high-strength form of ketamine, a powerful and addictive medical anaesthetic that is often taken by drug abusers as it can produce hallucinations.
NICE questioned the trial data, saying there was not enough evidence of long-term benefit and that offering the medicine was ‘unlikely to be an acceptable use of NHS resources’.
Janssen, the drug firm behind Spravato and a subsidiary of US pharmaceutical giant Johnson & Johnson, hit back, claiming NICE acted unfairly and branded the appraisal process ‘not fit for purpose’. In June, Janssen appealed against the ruling – and in a move that surprised many, the company was backed by the Royal College of Psychiatrists.
In emails seen by The Mail on Sunday, the Royal College accused NICE of being ‘unreasonable’ and claimed the snub ‘discriminates against patients suffering from mental disorders’. The bar, in terms of evidence required, had been set so high it would prevent any drug for treatment-resistant depression from being approved, it added.
Last week NICE announced its appraisal committee will reconvene in October to explain its rationale. Representing the Royal College at the hearing will be Dr Rupert McShane, from Oxford Health NHS Foundation Trust, who worked as a researcher in trials of Spravato and has sat on advisory boards for Janssen.
Dr John Read, Professor of Clinical Psychology at the University of East London, said he was alarmed by the Royal College’s intervention, claiming it was ‘siding with the drug company’s woefully biased position instead of prioritising patient wellbeing and safety’.
Depression affects roughly five per cent of adults in the UK, but a third of those do not find relief from antidepressants, most commonly selective serotonin reuptake inhibitors (SSRIs), which work by topping up levels of the chemical messenger serotonin in the brain.
Esketamine, the active substance in Spravato, works differently to SSRIs by increasing levels of a substance called glutamate, which helps brain cells function better.
Scientists have long looked at ketamine’s potential use as an antidepressant, but studies show that stopping it after regular use can trigger withdrawal symptoms, including anxiety and tremors. But as esketamine is more potent, smaller amounts are needed to have an effect on the brain.
This, say advocates, means side effects are limited. Yet the European Medicines Agency identified risks of treatment, including ‘transient dissociative [trance-like] states, perception disorders, disturbances in consciousness and increased blood pressure’. Patients using Spravato have reported ‘feeling drunk’.
Carmine Pariante, Professor of Biological Psychiatry at King’s College London, said he supported the Royal College: ‘We know how this treatment works and there is clinical trial evidence that it is effective in those who have not responded to any other antidepressants. We’re limited in what we can offer these patients. I’m surprised NICE did not see it as a positive step.’
Yet Joanna Moncrieff, Professor of Critical and Social Psychiatry at University College London, said: ‘Esketamine is expensive and the adverse effect profile is worrying. I think the push for it is primarily coming from the pharmaceutical company and psychiatrists who want to find a drug to solve problems that medication can’t fix.’
A spokesman for the Royal College of Psychiatrists said: ‘We are disappointed in NICE’s decision. In relation to our appeal, all rules on declaring of conflicts were abided.
‘The college will keep engaging with NICE to ensure that patients with treatment-resistant depression can access as many treatment options as possible.
‘Based on our consultation process with members, the college believes that with the appropriate safeguards in place, [esketamine] would be an important new treatment option for NHS patients, but for now it will continue to only be available privately.
‘It is vital that NICE’s decision does not prevent further research into the effectiveness of esketamine in helping treatment-resistant depression.’
The Spravato Controversy:
Christopher Lane, PhD
@christophlane
6 deaths occurred in the drug arm of other esketamine studies, 3 of them suicides (at 26 hours, 5 days, and 6 days after esketamine administration). Two of the patients had shown no previous signs of suicidal ideas.
Thread
https://twitter.com/christophlane/status/1580607377153622018
The Spravato Controversy: A Row Over the Drug’s Efficacy Compels a Reassessment of its Approval
By
Christopher Lane, PhD
October 13, 2022
https://www.madinamerica.com/2022/10/spravato-controversy/
The UK’s national drug regulator last month rejected an esketamine-based nasal spray that would have cost the National Health Service—and, by extension, the British taxpayer—almost £1,000 per patient per weekly dose.
At discounted rates, the same treatment costs almost $3,000 in the U.S. for the first month alone. Unusually, in this case, the drug maker—Janssen, a subsidiary of U.S. pharma giant Johnson and Johnson—responded to the decision by calling it, the evaluation process and, by implication, the regulatory agency itself “not fit for purpose.”
First reported in the national Mail on Sunday, the row is notable because the UK’s Royal College of Psychiatrists, the field’s professional and lobbying association, not only joined in but took the drug-maker’s side, accusing the agency of being “unreasonable” in rejecting esketamine for NHS treatment on the basis of high cost and required hospital supervision. The decision was said to “discriminate” against patients with acute depression.