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Bait and Switch: the Great Ketamine “Breakthrough”

Ketamine has been available in our office for years as a compounded version that you can take home and use. It is highly effective. This new version is a twist on an old drug.

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:

  1. 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.
  2. 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 monthswere 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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