extending the risk…

Posted on Monday 21 December 2015

Continued from a worksheet post…

In April 2015, the FDA approved a new Atypical Antipsychotic, Brexpiprazole [Rexulti®]. Around the same time, there were two articles about the Brexpiprazole clinical trials, both released on-line ahead of print in prominent journals [see the spice must flow…]. But there were some odd things about those articles. Each one had only one academic author – the rest were pharmaceutical company employees. But there was more [see anything goes…] – the academic authors were from the same department of psychiatry, the same institute [Feinstein Institute for Medical Research], with similar conflicts of interest, and the medical ghost-writers were also from the same communications firm [QXV Communications, Macclesfield, U.K.]. These were the studies that the FDA evaluated in the approval process. These articles were virtual clones.

Brexpiprazole [Rexulti®] was approved and launched just as Aripiprazole [Abilify®]  went off-patent. And speaking of clones, Aripiprazole and Brexpiprazole sure look like clones to me when I compare their chemical structure:
But that’s not all, folks! Another odd thing, the initial FDA submission covered two indications – and both were approved in April 2015. I’ve never seen that before:
Lundbeck Press Release
September 24, 2014

H. Lundbeck A/S [Lundbeck] and Otsuka Pharmaceutical Co., Ltd. [Otsuka] today announced that the US Food and Drug Administration [FDA] has determined that the New Drug Application [NDA] for brexpiprazole for monotherapy in adult patients with schizophrenia and for adjunctive treatment of major depressive disorder [MDD] in adult patients is sufficiently complete to allow for a substantive review and the NDA is considered filed as of 9 September 2014 [60 days after submission]. The PDUFA date is July 11, 2015…
Then in August 2015, another really odd thing. There were two Brexpiprazole articles by the same authors on the same topic published back to back in the same issue of the same journal [JCP] [with only one academic author each – the same academic author]. This clone thing is getting out of hand!
by Thase ME, Youakim JM, Skuban A, Hobart M, Zhang P, McQuade RD, Nyilas M, Carson WH, Sanchez R, and Eriksson H.
Journal of Clinical Psychiatry. 2015 76[9]:1232-1240.
by Thase ME, Youakim JM, Skuban A, Hobart M, Augustine C, Zhang P, McQuade RD, Carson WH, Nyilas M, Sanchez R, and Eriksson H.
Journal of Clinical Psychiatry. 2015 76[9]:1224-31.
That really is a first. Like the two Schizophrenia articles, the augmentation articles were submitted around the same time as the application to the FDA. And as you might have guessed, the ghost-writing firm for both is our friend QXV Communications, Macclesfield, U.K. also. Just one more thing to mention. If you look on clinicaltrials,gov at the trials for Brexpiprazole, this is what you’ll find:
You can’t miss the emphasis on MDD trials for this antipsychotic drug [meant for Schizophrenia]. And as for the odd stuff, they don’t seem to mind that the experommercial nature of these articles [industry funded, industry run, industry written] is blatantly obvious, or that it’s crystal clear that the market they’re aiming for is the augmentation-of-treatment-resistant-depression market, or even that Brexpiprazole is an obvious patent extender clone for the wildly successful Abilify®. I expect they’re going to sell it as the hot new drug by detailing doctors, and even here in the woods of Appalachia, we’re already seeing people [non-psychotic people I might add] showing up taking it.

I’m not in love with this story about the marketing practices of big PHARMA, but that’s not really any of my business. But there’s something else that is. When I first started working as a volunteer in the clinics up here, it seemed like everyone was taking Seroquel®. I couldn’t figure out why. At the time, it was the number one selling drug in the country. That’s actually what got me blogging here in the first place. Over time I finally got every non-psychotic patient off of the Seroquel® – worried about Tardive Dyskinesia and the metabolic syndrome, particularly with long term use. I was kind of proud about getting them off that drug. Recently, our clinic has expanded its scope, so there has been an influx of new patients, at least new to me, and guess what? – a lot of them are on Atypical Antipsychotics [not just Seroquel®, but Abilify® and the others]. But here’s the bad part, I’ve got three of those new cases who have definite early Tardive Dyskinesia [a lot for my small practice]. Mercifully, two seem to be waning now they’re off of the drug [fingers crossed], but I’m afraid one is probably around forever. They’ve all been on the drugs for a long time [which is what happens these days]. And I doubt such symptoms happen in short trials.

The Editorial in December’s American Journal of Psychiatry – Adjunctive Ziprasidone in Major Depression and the Current Status of Adjunctive Atypical Antipsychotics  by J. Craig Nelson, M.D. who is the same guy who coauthored the very first augmentation study and has subsequently written extensively on the subject [see a worksheet post…] – ends with this:
Although the acute efficacy of the adjunctive atypical antipsychotics is well established, the major shortcoming is the dearth of long-term placebo-controlled studies that would inform clinicians about persistence of efficacy or burden of adverse effects. Only two studies have been performed. In one, risperidone failed to have a significant effect in preventing relapse; however, methodological problems may have contributed to the result. A recent 26-week relapse prevention study of the olanzapine-fluoxetine combination showed a significant advantage for the combination. In that trial, after 6–8 weeks of acute treatment with olanzapine and fluoxetine and 12 weeks of stabilization, patients were randomly assigned to the combination or to fluoxetine plus placebo. A time-to-relapse analysis significantly favored the combination. Under the primary definition of relapse, 15.8% of the patients on the combination relapsed, compared with 31.8% of the patients on fluoxetine. Nevertheless, the paucity of long-term controlled studies for the atypical agents limits our understanding of the persistence of efficacy and of side effects that may increase or emerge with time. This leaves the clinician whose patient has responded to acute adjunctive treatment with little information for weighing the risks and benefits of continuing the adjunctive agent.
Good for him for saying that part at the end. But I know the answer. Once people start these drugs, they just keep taking them and nobody takes them off. My cases of Tardive Dyskinesia are a testimonial to what can happen – a tragic testimonial.

So that’s why I liked the Spielmans et al meta-analysis [the extra mile…]. It showed us that from the patients’ own ratings, they weren’t getting that much benefit – a very important piece of data. And for that matter, Spielmans et al documented the Adverse Events including the high incidence of Akasthisia [a Tardive Dyskinesia harbinger] with Abilify®. So I know why I’ve been so stuck on this business of Atypical Antipsychotic augmentation of the so-called treatment-resistant-depression. All of these Atypicals may have a low moderate effect on TRD symptoms, sure enough, but these drugs are time-bombs [particularly] if they are used long term [and they are used long-term!]. So if nobody’s really looked long term in the last 16 years, Why the hell not?

They’re not just using Brexpiprazole to extend the patent of Abilify®. They’re  extending the risk in the process – a big risk that’s been largely ignored…

Note: The only long term Incidence of TD study I know of is the 2010 European Schizophrenia Study [sponsored by Eli Lilly]…
  1.  
    December 21, 2015 | 2:25 PM
     

    I hope the Yatham paper in Mol. Psych. inspires some copycats in the unipolar depression literature. The pharmaceutical companies are going to work very hard to market their drugs for a condition with ten times the prevalence of schizophrenia. It would be nice to have some actual evidence whether these augmentation effects are durable; or if they’re just accelerating what would otherwise happen on its own.

    [I believe this is the paper Pat is referring to, 1BOM]

  2.  
    Altostrata
    December 21, 2015 | 5:07 PM
     

    I have several people on my site who have developed tardive dyskinesia after being prescribed a “low” dose of an atypical antipsychotic for sleep or as “adjunct” to an antidepressant.

  3.  
    Johanna
    December 22, 2015 | 2:32 PM
     

    I’m thinking many of the people Altostrata has heard from were given the “Little Baby Dose Line.” That’s a marketing pitch aimed at calming the fears of patients who wonder if they should really be taking anti-psychotics for “incompletely remitted depression” — or even “treatment resistant depression” if it’s not totally disabling.

    “Don’t worry. These are little baby doses we’re talking about — just a fraction of what we give people for schizophrenia!”

    It works to calm nervous doctors too — pretty soon they are handing out “little baby doses” of neuroleptics as casually as they hand out Ambien or Ritalin. Only trouble is, it’s a bit of a scam. One reason: the competing metabolic pathways of these drugs can double or even triple your blood level of the antipsychotic when you take it in combination with certain antidepressants. A bit of expose on RxISK.org regarding this: http://rxisk.org/abilify-from-the-inside-out/

  4.  
    Altostrata
    December 22, 2015 | 2:47 PM
     

    Very true, Johanna.

  5.  
    Catalyzt
    December 22, 2015 | 10:18 PM
     

    Hey, folks,

    What is everyone seeing for the very first symptoms of TD that everyone is seeing? Are there any prodromal symptoms that occur before it sets in?

    I know this is covered in a million different articles, but I’m much more interested in clinical observations. What I’ve seen that made me suspicious– and I saw it only a couple of times– was sort of a restless lower lip, like when people have been snorting lots of blow and/or a kind of simian lip puckering.

    It came on very fast for my client, and he/she and the prescriber were both very dismissive of it.

    Thanks,

    Thanks.

  6.  
    December 23, 2015 | 12:24 AM
     

    Catalyzt,

    I think it’s the stereotypy. There are multiple versions of abnormal mouth/tongue movements that may appear [“oro-buccal-lingual stereotypy“], but the thing that catches my attention is that whatever they are, they’re repeated.

  7.  
    Catalyzt
    December 23, 2015 | 9:08 PM
     

    Thank you, Mickey. I had not seen the term “stereotypy” before, although– strangely– “oro-buccal-lingual” was familiar.

    The wiki on stereotypy in animals was very interesting. (Sorry to hijack the thread here– I know the topic is TD from augmentation with atypicals, but the environmental/cultural piece of this got my attention.)

    Stereotypical behaviors are thought to be caused ultimately by artificial environments that do not allow animals to satisfy their normal behavioral needs. Rather than refer to the behavior as abnormal, it has been suggested that it be described as “behavior indicative of an abnormal environment.”[18] Stereotypies are correlated with altered behavioral response selection in the basal ganglia.[15] As stereotypies are frequently viewed as a sign of psychological distress in animals, there is also an animal welfare issue involved. (Yeah, no kidding!)

    Stereotypical behavior can sometimes be reduced or eliminated by environmental enrichment, including larger and more stimulating enclosures, training, and introductions of stimuli (such as objects, sounds, or scents) to the animal’s environment. The enrichment must be varied to remain effective for any length of time. Housing social animals with other members of their species is also helpful. But once the behavior is established, it is sometimes impossible to eliminate due to alterations in the brain.

  8.  
    Sally
    December 29, 2015 | 11:02 PM
     

    Johanna,

    Thank you so much for the link you provided – that information has made a whole piece of what happened to us make so much sense! The site is truly an amazing service

Sorry, the comment form is closed at this time.