Thursday, September 3, 2009

Saphris: It's Different without Actually Being Different

On August 14th, the FDA approved Schering-Plough's second generation antipsychotic drug Saphris (asenapine) for the acute treatment of schizophrenia, and the acute treatment of mania/mixed episodes associated with bipolar I disorder (1).

Question: Should I, at all be concerned that there are more actual published peer-reviewed articles of this drug being tested in rats (2, 3, 4, 5, 6 ) than in humans (7; seriously, this is the only published peer-reviewed article I can find)?

I'm not going to discuss the controversy surrounding this drug (interested persons go here: 8, 9).

What I'm going to address is the marketing angle that is being used to push this product. Namely, that its "unique human receptor signature" (10) confers a "favorable clinical profile" (7) over other antipsychotics; specifically, that it has a "high degree of safety and tolerability" as well as being a "useful option in patients with negative symptoms" (7).

Here are the various receptor affinities for the drug:

What does this mean? "Asenapine has high affinity for an ensemble of receptors, including the 5-HT receptor subtypes 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7; adrenoceptor subtypes alpha1A, alpha2A, alpha2B and alpha2C and dopamine D3 and D4 receptors. The interaction of asenapine with each of these receptors occurred at a higher affinity than that for any of the other drugs tested" (10). In other words, Clozapine is for pussies, Asenapine is hung like horse!

The skinny of this article is that each of these receptors, when blocked by this drug, may confer improvement in emotional and cognitive functioning.

Oh you didn't know? Apparently other antipsychotics don't improve the negative and cognitive symptoms of schizophrenia, which was pointed out ad nauseum in the only published peer-reviewed study I could find (7): "Although all antipsychotics ameliorate such symptoms to varying degrees, none are completely effective in all symptoms domains. Thus, there is a need for newer, more effective agents to treat the the full range of symptoms expressed in schizophrenia." Two paragraphs later, "Current pharmacotherapy for schizophrenia is limited by inconsistent or inadequate control of negative, affective, and cognitive symptoms, as well as by distressing side effects." In case you're retarded, they reiterate, "Antipsychotic pharmacotherapy offering improved effectiveness in treating the full range of positive, negative, affective, and cognitive symptoms associated with schizophrenia, plus improved tolerability, therefore remains an important unmet clinical need."

It's common in these types of articles to state the same message throughout the paper (i.e., abstract, introduction, discussion); however, all this was in the introduction only, and in adjacent paragraphs.

The manufacturer is pushing the drug on the premise that it improves the negative and cognitive symptoms of schizophrenia better than other drugs, in addition to having a better safety profile.

The safety profile angle has been used before (11). While the drug demonstrated less weight gain compared to risperidone or olanzapine, it has an elevated level (18%) of extrapyramidal symptoms (EPS) comparable to first generation antipsychotics (12).

Don't worry folks, there's a way to obscure that little fact. All you have to do is generate a drug trial where you compare the drug to the very potent D2 blocker, haloperidol, thus making any incidence of EPS seem minuscule (13).

The sample size of this study (7) is quite small compared other clinical trials (n=174). At the end of 6 weeks, only 73 subjects completed the study. That high rate of attrition is common for schizophrenia trials, keeping in mind that the patients included in these types of studies are pretty high functioning (no co-morbid medical or psychiatric illnesses, able to provide consent).

Normally, this is the part where I copy the result charts for you visual learners out there, but the cocksuckers secured the PDF file, thus preventing me from copying the data. Anyway, "at end point, mean changes from baseline were -15.9 with asenapine versus -5.3 with placebo (p<.005); the change with risperidone (-10.9) was nonsignficant versus placebo." No statistical comparison was conducted between the two active treatments, but a 5 point difference most likely is not signficant.

What about those pesky positive symptoms? "At end point, mean change from baseline were -5.5 for asenapine versus -2.5 for placebo (p=.01); change with risperidone (-5.1) was also signficant versus placebo (P<.05)."

And the negative symptoms? "At end point, mean changes from baseline were -3.2 for asenapine versus -0.6 for placebo (p=.01); change with risperidone (-1.05) was nonsignificant versus placebo." It appears that the drug is actually better at improving the negative symptoms of schizophrenia. Not quite, "Mean baseline scores were 24.1, 23.1 and 21.9 for the asenapine, placebo, and risperidone groups, respectively." If you subtract the changes, total mean scores are 20.9 and 20.85 for the asenapine and risperidone groups, respectively. The asenapine group was more severe to start with, thus allowing more room for improvement. Moreover, the asenapine mean changes were no greater than the changes produced by iloperidone, haloperidone, and risperidone in this study (14). In other words, asenapine is more of the same.

Next comes the faulty logic and far reaching conclusions of the discussion section. In reference to the drug's "unique human receptor signature" the authors state that "this pharmacologic profile may explain, at least in part, the effectiveness and toelrability of asenapine in controlling a wide range of schizophrenia symptoms." If one reads a lot of research, then you'll know that these results are no different than any other drug on the market. This is pure advertising. Personally, I cannot wait for the next conference I attend. I can't wait to see the pharma puppet actually try to push this "unique human receptor signature" shit on his audience.

"In conclusion, this double-blind, placebo-and risperidone-controlled 6-week study showed that asenapine 5mg b.i.d. was effective and well tolerated in the treatment of acute schizophrenia and may be a useful option in patietns with negative symptoms." If you say it enough times, eventually it becomes true...

This study plus one more were what the FDA use to approve this drug for use in schizophrenia. All other research for this drug can be found in a single issue of Schizophrenia Research (Volume 98), which is a supplement issue, and it includes only abstracts that were presented at a conference (XIVth Biennial Winter Workshop on Schizophrenia and Bipolar Disorders). Stingy douchebags!

That second study (13), had a larger sample size (n=458) and compared asenapine to placebo and haloperidol. Haloperidol match asenapine on the primary measure, but for some reason, haloperidol's effect on negative symptoms were not reported, only asenapine's were (mutherfuckers!).

Saphris is going to be pushed as being good for negative symptoms. That's what I took away from these advertise, err, research articles. I tried to find more data at clinicaltrials.gov (15), but that was fucking pointless (Usually, when I jerk off I have something to show for it).

Another drug (lurasidone) is also ready for an FDA indication for schizophrenai as well (16). Guess what angle they're going with? "It's among the most benign of any antipsychotic drugs, clearly better than olanzapine, clozapine and Seroquel," Should I even waste my time with this drug?

ResearchBlogging.org

Potkin SG, Cohen M, & Panagides J (2007). Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. The Journal of clinical psychiatry, 68 (10), 1492-500 PMID: 17960962


Update: (February 8, 2010) . The February 8th issue of the medial letter (Vol 52, Iss. 1331) they have a piece on Saphris 
"ADVERSE EFFECTS — The most common adverse effects occurring in >5% of patients taking asenapine and at least twice as frequently as in those taking placebo were akathisia, oral hypoesthesia and somnolence in schizophrenia trials, and dizziness and extrapyramidal symptoms other than akathisia in bipolar trials. Weight gain in clinical trials was greater than with placebo, but less than with risperidone or olanzapine."
"DRUG INTERACTIONS — Asenapine serum concentrations may increase when the drug is taken with a strong inhibitor of CYP1A2 such as fluvoxamine (Luvox, and others). Asenapine is a weak inhibitor of CYP2D6; serum concentrations of paroxetine (Paxil, and others), which is both a substrate and inhibitor of CYP2D6, increased almost 2-fold when taken with asenapine."
"CONCLUSION — Asenapine (Saphris) is a new second-generation antipsychotic agent. Available data on its efficacy are not impressive. It can cause extrapyramidal symptoms and weight gain. Because it has poor bioavailability when swallowed, the drug must be administered sublingually to achieve therapeutic blood levels; whether schizophrenic or acutely manic patients will be able to adhere to this requirement is an additional concern."  

29 comments:

Neuroskeptic said...

I wish instead of spending so much time and money fudging the data like this a drug company would just have the balls to say "This drug is probably no better than chlorpromazine, but we'll pay you $5 every time you prescribe it. And you get a free pen."

"The skinny of this article is that each of these receptors, when blocked by this drug, may confer improvement in emotional and cognitive functioning."

For this to be true of course you would have to believe that most of the receptors in the human brain were just put there by God to torment us, rather than doing anything useful.

P.S They locked the PDF but couldn't you print screen?

condor said...

Great post! Thanks for the link, in the body of yours, to mine.

I hope to offer some additional observations, on yours, over the long Labor Day Weekend, courtesy of a co-hort of mine, Salmon. . . . do click through now, but expcially so, after Monday night -- as I bet he will have much to say about yur take -- and favorably so.

I do think, per your footnote 7, there are about five studies in humans -- as set forth in the over 1,000 pages of unlocked PDF files the FDA "liberated" as it approved asenapine.

Namaste,

-- The Condor

Cypher said...

"...but the cocksuckers secured the PDF file, thus preventing me from copying the data..."

if you're using Windows, did you try, while looking at the data, pressing Ctrl - Alt - Print Screen, then opening Paing, then pasting with Ctrl - V, then saving the file.

Or is it really super secure?

Cypher said...

Oops, by Paing I meant Paint.

Anonymous said...

The asenapine FDA reviews are currently available but I don't know for how much longer. When FDA approved asenapine they did not include the reviews in the usual database for released reviews. Even if they are available in the future the way they published them is going to be very very difficult for anyone to find in the future. This looks very suspicious to me.

Salmon

Another scientist who can't stand bad science (or corruption).

Paul said...

Haloperidol is a drug that's always used as a comparison in new AP drug trials. The Cochrane Review reviewed the data on Haloperidol and concluded that, due to its propensity to casue a number of adverse effects (movement disorders namely),it was "somewhat surprising that" it is "used so widely as a comparison for new medication".

http://www.cochrane.org/reviews/en/ab003082.html

Great blog by the way. Just found it.

Jack McCullough said...

Great blog and great post.

I just linked and quoted you in this post:
http://beyond-vsh.blogspot.com/2009/10/psychiatrists-to-big-pharma-get-lost.html.

I'm going to follow you for more insight into this stuff.

Jerod Poore said...

For anyone who might be interested, we have three people at Crazy Meds with various forms of treatment-resistant bipolar disorder who were prescribed Saphris in addition to other medications they currently take.

Everybody liked the effects at first. Two people had to stop taking it after less than a week due to EPS, one of them also had aggravation of his manic symptoms.

One person is still on it with good results.


The taste and literal foaming at the mouth was universally despised. Given how people with bipolar II complain about Lamictal's taste that could make it a non-starter for a big chunk of the bipolar population.

This is now my new favorite neuropsychopharmacology blog.

Anonymous said...

Great blog post. I love your informed and skeptical point of view. I just found out about this drug (not being a very astute reader of journals at this point), and I really appreciate your post.

Anonymous said...

Love the blog. I also seem to really like Saphris so far. I know this dates back a bit. I was started on it and I feel better than I have in two years. As a psychopharmacology buff (I went to school but could not afford to become a pharmacist, so I'm just an amateur). But I have Schizoaffective disorder and Schizotypal PD, and I believe it's quite mild compared to most Schizoid illnesses. My point is that you debated about the effectiveness of Saphris for "positive" symptoms. For me, at least, my positive symptoms have greatly improved. I haven't heard this much silence in a long time. As far as the negative symptoms, Saphris is doing well at that too. I've been on more than fifty psychiatric medications and this one seems to be a winner for the moment. Let's see if it "poops out." You rule. Keep up the blog!

Anonymous said...

i smell a pharm rep to the north

house music all night long

ps
You Rule!

Anonymous said...

the maltese falcon is greatly appreciated.
I specialize in maltese falcons and other such things, as well as kicking big pharma ass.
this is off topic, but I'm so happy to find this blog.
google 'disposable heroes james elliott'
that was my work.
pfizer. yeah, those guys. I'm still alive! yippee!

so, to see someone in neurology willing to post this blog is a good sign, that people are willing to discuss these issues, that they are willing to acknowledge that using compounds retro-engineered from snake toxins and laundering research studies with other research studies should be monitored (and, in my belief, fined or shut down) well,
I wish I had seen this blog in 2008. I felt so alone that year, knowing that the VA and the DOD had written at least 200,000 prescriptions to soldiers and returning veterans, as well as their caregivers,
for CHANTIX.
Go Figure. I felt like I was the first person walking into Auschwitz.
I know what he felt like mentally. Something had to be done. It wasn't enough, but it at least got the testing on PTSD subjects stopped................
thanks for this blog. keep blogging.
think about your own security.
these people are ruthless. I know.

Kim said...

Thanks for the info and skepticism. My doc gave me a sample because I told her the songs wouldn't stop. (She had warned me the combo of drugs could cause it. *grrr*) I can't type that sentence without wanting to smack myself.

One sublingual and I thought I was on a bad acid trip. Not only does it taste like poop, it knocked me on my butt. I was supposed to be "clear headed in the morning" but don't remember--and not willing to take any more horse tranquilizers. I'll keep my songs.

Anonymous said...

I do find your point interesting. However, I just thought you might want to hear what I have to say about it. I have Bipolar disorder. I have been on numerous drugs including other atypical antipsychotics such as Seroquel. Saphris really saved my life. I haven't felt this good in a very long time. Plus, I don't experience as many sideffects like weight gain. Just thought you might want the opinion of someone who is on the drug.

NeuroPsych said...

Anon, if it works for you, that's great. It really is. I'm more annoyed by the lack of innovation in the field and the constant re-branding of each drug as "the next best thing" when it really is the same thing.

Anonymous said...

Hi everyone BJ here, I have had a severe sleep disorder/ agitation disorder for years. I have only been able to find relief from Luvox, and that was not near enough.

Two things first off- They make a black cherry flovor, I am not a "tough" guy, its really tolerable ( the taste) if you compare that to the illness...


Second- I am not in the pharmaceutical field, but I can tell you I have tried over 50 medications, nothing has come close to Saphris for relief for me. Clonazepam, does not get the "edge" of my agitation off.

So all of the skeptics out there, please keep an open mind, I did, and now I am on it for 7 weeks, and its made an emence difference in my life, it has given me back a life. The only downer so far, I have gained weight on it. No other side effects from somoene who can't even tolerate 5 mg a day of lamictal. ( thats how sensitive I am).

I normally don't post, so I want to encourage other "not poster" people to post, we need to hear the truth from all people.

Anonymous said...

Why didn't my comments publish...

Anonymous said...

My daughter was taking just seroquel for her "severe psychosis" (not old enough to be diagnosed with schizophrenia. It did well for a time, but then symptoms started returning even on 800 mg of seroquel. Dr. started her on Saphris and she's been on it for several months. Doing well mentally, really, but has a rash on her thighs and has recently experienced rapid heart rate. These are side effects. Will see what Dr. says, but she's doing SO well mentally, I'd hate for her to have to stop it.

Anonymous said...

I am interested to try this drug since invega just failed. I became extremely ill, wouldnt wish it on my worst enemy. Glad to see someone out there is watching out for us. I wish a company could please start making akineton again so I can start living. they got rid of my symtoms of seroquel eps, stiff muscles. I am getting tired.

Tam said...

My name is Tam. I have bipolar 2, PTSD, Generalized Anxiety Disorder and Sleep Disturbance NOS. I was diagnosed in 2003 and have been faithfully taking my medication regimen since. I experience auditory hallucinations which present themselves with loud intrusive music and whispers. This mostly happens at night. I also have episodes when I become hypomanic and then can be depressed within one day. When I become hypo manic, I often have odd thoughts that are off behaviors that would be hurtful, illegal or even fatal. I am currently going to start my Ph.D program in September. It is upsetting to me to have this illness. I have plans, goals, dreams and a beautiful family that I love. But this illness does what it wants, when it wants. Went to the doctor today and she gave me samples for Saphris. I did a little research and the side effects seem serious. I am on Paxil and it said something about the medication altering the absorption of that med.
I would like to hear more positive stuff about people’s experiences on this med. I have read and heard the opposite but would truly like to hear about specifics in regards to how this medication helped you. I have not started the med yet. It is sitting on my side table. I am afraid to alter my meds. Whenever I add or change a medication, I have scary results. The doctor wanted to put me in the hospital to adjust my meds but I said no. I have no insurance and allot of responsibilities. Also, the main reason is that I am too paranoid to admit myself to a hospital.

Tam:)

Anonymous said...

I was just given Saphris yesterday after being the 1.3/1000 people using Lamictal to get Stevens-Johnson rash. I am terrified to start using it. It's there on my table as well, and I am afraid of what happens if I continue not to take anything. I would also like to hear more about positive experiences with the drug.

Tam said...

He there, got the comment. I never did take it. I found out that I was so enemic that I should probably not even be alive..lol...so yesterday I had a 10 hour IV Iron infusion. It will be a few weeks until I feel better and then I will reavaluate the possibility of taking that medication. You can contact me on my blog http://bipolardaytodayreality.blogspot.com

It is for peopple that are bipolar and need to talk, get stuff off of their chest or just read other people's struggles.

Tam

Adversary said...

Hey, it was nice finding your blog. Now I would like to leave my experience with saphris for others who plan on taking or have taken it.

At first, I thought Saphris was a 'life saver'. It tapered me off of ambein. I have bipolar and it made my nights where I couldn't sleep bearable.I felt pretty steady but I would often have higher and higher manic 'episodes' on this medication. I don't know if I would blame the medication or what, but they would come completely out of the blue. Dancing around in the metro station blasting your ipod while dancing around people on a random tuesday is fun and all but they seemed to happen more frequently on this medication then not. Also I started to have muscle stiffness in my neck, which felt like I was doing coke all the night before. Also, I have been sick with nasal congestion and a sinus infection for months now, which is interesting after I looked at this document. http://4.bp.blogspot.com/_M_OtwEgZgAk/Sm_MdmRwQ1I/AAAAAAAADHo/H8_QYAy3Z6w/s1600-h/SGP-Asenapine-FDA-07-28-09-.jpg
I don't know if I can blame anything on this drug or if it was a coincidence but I stopped it as soon as I started to feel as if I felt toxic. I did gain 25 pounds and I know that was from the drug. I have been the same weight for years. I started researching this drug to become a more informed consumer and realized that anti psychotics seem very risky. After this experience, I don't think I trust any pharma drugs now.

neurovx said...

"This drug is probably no better than chlorpromazine".
I started taking Saphris a couple of weeks ago and it has helped a lot.
I studied biochemistry in college, and looking at this study,I find no flaws. I think, Neuroskeptic, that you are letting your anti-pharma stance cloud your judgement. You are not rational. A "big pharma" company can be "bad" but still produce a wonder drug. It's not black and white. It is a shade of grey.

Anonymous said...

Bi-polar, anxiety, panic, clinical depression
This drug saved my life. I accidently ran out and ,BOOM, suicidal ideation, anxiety,ect, through thr roof. Just got some more today thank god. I've been on the edge of going to the hospital for a week. When I'm on Sapphris I feel like there is a reason to live. No side effects for me at all.

leeboo23 said...

Dude...you're blogs are the shit. My boyfriend and I both have personality disorders, mine your highly treatable Borderline and the lesser known Dependant personality disorder, his is comorbid: scitzoid personality disorder, attachment disorder and the ever lovely bi polar II with rapid cycles. HIS doc just put him on the Saphris and we are just praying to whatever God might be up there torturing us with these annoying receptors in our brains, that this med gives him a reason NOT to hate all other humans and just plain enjoy life. Not holding my breath, but I'll certainly post his results in a few weeks. Oh, and are you really suprised they locked the PDF file?? lol

Anonymous said...

This drug has been the best thing that has happened in my life. My wife has been diagnosed with bipolar, and more recently borderline personality disorder. She has experienced paranoid delusions that sound like schizophrenia, but I have never heard that as a diagnosis. She started on Saphris a couple of months ago and since then she sleeps well, gets up in the morning, is friendly and cheerful, does laundry and housework instead of sleeping all day, and is generally interested in life for the first time in years. Previously she has been on every psyche drug known to man and has NEVER had a response anything close to this.

Smitty said...

My psychiatrist gave me Saphris, when I wanted to wean off the Seroquel XR.

He actually did not taper me off the Seroquel at all, just did a replacement with "whatever" dosage of Saphris would work for me.

I am one of those folks who does best weaning off medications, once my symptoms are not active, as sleep loss, coupled with unrelieved anxiety, is the trigger of my psychotic symptoms.

Once I am no longer anxious and have my sleep patterns normalized I really don't need an "antipsychotic" per se.

When the doctor "replaced"' the Seroquel XR with Saphris I had some slight shivering the first night and it increased terrifically the second night.

I have never felt more abandoned. We did a quick switch back to the seroquel XR, and now, a year later, I am successfully weaned down to lowest dosage of seroquel.

I take it at night, it helps me stay asleep a solid eight hours, so it is hard to convince myself that I am actually doing anything more to prevent psychosis, than get good sleep from this medication.

But the real point of my comment is to ask you, Have you encountered any research which explains the shivering side-effect of Saphris? I seem to be in a very small minority of folks who experience this.

I would still like to understand the mechanism.

Best, Victoria

Anonymous said...

Started out well. Found I was sleepy and slept. The taste is so awful that I bought a throat lube, because I was awakened by choking, and kept on galloping. I am big but not as big as a horse, so doses were appropriate. After months I was having a bad trip, a bad, bad, trip.