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?



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."