Furious Seasons

March 24, 2009

FDA's Lexapro For Teens Approval Creates Doubt About FDA Approval Process

No matter where any of you stand on the pro-meds/anti-meds divide, I suspect that all of you are interested in drugs going through appropriate clinical trials for real psychological diagnoses, being appropriately and consistently vetted by the FDA, and, if approved, being labeled with appropriate warnings about side effects, as well as having clinical studies published in medical journals where one and all can assess the results. That sort of process has, in my opinion, broken down at the FDA, most recently with regard to the agency's recent approval of Lexapro for major depression in adolescents aged 12 to 17. I'm utterly baffled by the FDA's approval process for the drug.

First, I need to let you know that I reached out to both the FDA and Forest Labs' outside PR person (they don't have their own PR shop apparently), but got no answer from either. Classic. Then again, the FDA still owes me all kinds of answers to all kinds of questions.

Second, the FDA has once again gone and approved a drug for use in kids with only one positive clinical trial, a trial that remains unpublished (unless PubMed is fibbing), despite the FDA's longstanding policy of requiring two positive clinical trials of a drug for approval. Both the FDA and Forest might claim there were two positive studies, but only the first study referred to on the drug's package insert was of Lexapro. The second was of Celexa. Yes, the FDA is now letting pharma companies obtain approval of drug's using data from other, similar drugs.

Even worse, Lexapro had at least two failed clinical trials in adolescents. More on that in a bit.

Here's how the insert describes the first study (download it here; the relevant text is on pages 22 and 23):

"The efficacy of Lexapro as an acute treatment for major depressive disorder in adolescent patients was established in an 8-week, flexible-dose, placebo-controlled study that compared Lexapro 10-20 mg/day to placebo in outpatients 12 to 17 years of age inclusive who met DSM-IV criteria for major depressive disorder. The primary outcome was change from baseline to endpoint in the Children’s Depression Rating Scale - Revised (CDRS-R). In this study, Lexapro showed statistically significant greater mean improvement compared to placebo on the CDRS-R."

I cannot find this study published anywhere. Forest didn't respond to a request to provide information about where it's published. So it's unclear how many teens were involved in the study and exactly how much efficacy Lexapro had over placebo. What's more, there's no way for clinicians, teens and their parents to evaluate the drug's safety and side effect profiles, which strikes me as being necessary information.

Here's how the insert describes the second study:

"The efficacy of Lexapro in the acute treatment of major depressive disorder in adolescents was established, in part, on the basis of extrapolation from the 8-week, flexible-dose, placebo-controlled study with racemic citalopram 20-40 mg/day. In this outpatient study in children and adolescents 7 to 17 years of age who met DSM-IV criteria for major depressive disorder, citalopram treatment showed statistically significant greater mean improvement from baseline, compared to placebo, on the CDRS-R; the positive results for this trial largely came from the adolescent subgroup."

Citalopram is Celexa, which is also made by Forest. I'm not a pharmacologist, but from what I understand Celexa and Lexapro are quite similar compounds ("me too" anti-depressants as some have called them), although they were different enough for each to receive a patent. Why the FDA would approve a drug based upon extrapolated data from a different compound is beyond me. The FDA didn't respond to my request for comment. I've not been able to find where this study is published and Forest didn't respond to my request for information.

Here's how the insert describes the failed studies:

"Two additional flexible-dose, placebo-controlled MDD studies (one Lexapro study in patients ages 7 to 17 and one citalopram study in adolescents) did not demonstrate efficacy."

Well, at least, the FDA got Forest to note this in the insert.

So we've got a drug now approved for teen depression but only one of the four studies was actually able to establish the efficacy of Lexapro in teens, that study is unpublished (as far as I know) and this approval really calls into doubt the FDA approval process. Risperdal was approved for use in alleged pediatric mania in August 2007, based upon only one study. These sorts of approvals are a bad trend at the FDA, one that I hope its incoming commissioner and deputy commissioner work to rectify.

Absent some logical answers from the FDA and Forest on all of this, I'd say the Lexapro for teens approval is suspect. Parents, teens and clinicians should proceed with caution.

Posted by Philip Dawdy at March 24, 2009 12:05 AM

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Comments

Lexapro / Celexa deal: Forest gets to have it both ways: You make a new drug so it can be under patent - you have to reach the criterion that it is different - slightly differnt chemically, slightly different in delivery (buffered, extended release, etc.), but then when it comes time to provide evidence that the new is effective, you just turn to the old.

Posted by: MedsVsTherapy at March 24, 2009 05:36 AM

The FDA would approve a drug based upon extrapolated data from a different compound because, basically, all the SSRI are alike. They all have listed in their insert for side-effects: mania, abnomal thinking, psychosis, paranoia, hostility, etc.

If people could only use common sense, they would understand why we are seeing so much mayhem i.e. school shootings, soldier suicides, etc., when almost all of these incidents took place while people were taking SSRIs.

The almost 3,000 stories of murder, suicide & mayhem on www.SSRIstories.com, taken from media articles, attest to this fact.

The FDA is making a sham of the Black Box warning for suicide in youth and of their own General Warning of March 22, 2004.

Posted by: Rosie at March 24, 2009 06:08 AM

Hm. FDA approves messing with our teens' minds, but denies the same teens access to OTC Plan B. I'm so disgusted with this agency.

Posted by: nvam at March 24, 2009 06:11 AM

Lexapro (escitalopram) is an isomer of Celexa (citalopram) which means they have the same atoms, different molecular structure. I.e. create a new compound that is just a little bit different and will work the same but has longer patent life and market the hell out of it.

Posted by: Doug Bremner at March 24, 2009 07:27 AM

Lexapro gave me the zaps too. And it obliterated my sex drive completely...

More importantly, I just want to put out there that Carlat apparently just put up a comment under his most recent Biederman post saying (allow me to paraphrase slightly), "The fact is Bipolar does occur in children "whether you want to call it bipolar, conduct disorder, or juvenile delinquency." "And antipsychotics do moderate behavior, although at the cost of significant side effects."

Wow. I have always respected Dr. Carlat and his work, but his careless, almost arrogant indifference to Biederman's acts is hard to look away from.

He has essentially said, I don't care either whether what you call bipolar in children is actually bipolar or not. That's basically Biederman's thesis.

How careless of him. I've really come to have a less rosy picture of Carlat's thinking imagined in my head. I feel like his piece in the NYT about the repping he did for (effexor?) or whatever, was just a sorry appology piece. I feel like the epiphany angle of it was totally phony. Like he had no idea what he was doing was wrong and that he wasn't choosing delicious little checks over actual patient care.

On Biederman,this is bland, childish denial on his part. It is supremely hypocritical, not to mention wrong, and I think it springs from his self-aggrandizing mission as well as his training with those arrogant pricks at MGH.

He is officially an unapologetic defender of Biederman and I feel like people such as Carlat who literally don't care about whether what gets diagnosed as bipolar in a 4 yr old actually is bipolar, are Biederman's worst enablers, and in an indirect way just as responsible for Rebbecca Riley's mangled care and eventual death.

And for anyone characterizing the people who comment here as Scientologists. Please, spare me.

And in the case of the "localdoc" who has been commenting over on Carlat's Biederman post, you're literally calling the patient or patientS possibly, of one of Biederman's colleagues at MGH child psychopharm, "Scientologists". Hell, you could be calling one of your patients a "Scientologist". What an ugly thing to realize.

...I've often wondered in my head, to entertain myself, what would happen if the "Church of Scientology" had this big dramatic schism or closing down, where it no longer existed and it just melted away like so many other faddish cults before it, and it was covered in the media and stuff. What would the American Psychiatric Association do then? haha What about the "localdocs" who smear the patients they've misdiagnosed and harmed as "Scientologists" over an internet comment thread? My guess is if there was only one Scientologist left on the planet and his name was Tom Cruise or Joe Jackson, or whatever, they'd still be calling their patients and detractors "scientologists".

It gets even more ridiculous when you think about it this way... I was raised Catholic and I don't even like being called Catholic. It's offensive, to me and my world view and is life-negating. If someone wanted to call me Catholic, they'd be awfully stupid, but at least they could say, well, you spent every sunday of your life for the first 15 years in a catholic church for an hour or so, and I couldn't contest that. But at this point I'm basically, rabidly anti-Catholic as well as anti-religion. Why would someone call me a Scientologist?

My doctor, who works at MGH, actually wrote that in my notes a long time ago, completely unprovoked. I had stopped taking my medicine because I had become a Scientologist. At 16! And this is a guy with a faculty appointment at Harvard medical School! You can just call you're patient a Scientologist? I didnt even know a fucking thing about scientology then and still don't now. I mean, what a psychotic thing to do, for a psychiatrist no less. (Obviously that angered me very much then.)

Hmmm, a 16 yr old stops taking his depakote and risperdal, for a bipolar disorder he was right about not actually having, because he at the age of 16 has become a Scientologist, despite the fact he is avowedly anti-religion, has no car, and dysthymic most of the time, or, because he is tired of explosive weight gain, and he hopes that if he stops taking his depakote his pubic hair will grow back?

Fuck a bat Biederman, you sick, Sociopathic bag

This is the kind of process, that will destroy a child's life, and probably does so routinely at MGH -- a process which Carlat is defending and enabling.

.........

Anyway... the Scientology thing is tired and old.

Again, Mormon's don't drink alcohol. Why wouldn't you call a recovered alcoholic in the Bronx a Mormon? Jackass.

Posted by: JC at March 24, 2009 07:31 AM

One of the big things I find appalling is that these approvals are based on 8 week trials with not one little hint about what happens after that. Certainly there is no indication anywhere on the insert that you're only supposed to take it for 8 weeks and there is the implicit assumption that this happy outcome they go to lengths to define (by suspect criteria) will continue on indefinitely. Anyone who has had any exposure at all to antidepressant treatment knows that this is not how it works. I believe drugs which are prescribed indefinitely for supposedly "chronic" conditions, as depression has become (after all it's a "brain disease"), need to be approved on the basis of long term studies. Then a more complete picture of how antidepressants work or don't work would become evident, that is, if the studies were done honestly and forthrightly.

Posted by: Sara at March 24, 2009 08:34 AM

The FDA would approve RAT POISON for depression and anxiety because that's just about what these drugs amount to...

Posted by: truthman30 at March 24, 2009 10:06 AM

I feel your frustration. When Abilify was approved for pediatric bioplar disorder, none of the studies were published (I could only track down a couple abstracts from poster sessions). After going back and forth with a drug rep, I still got nothing. Keep data secrete like this only serves to fuel distrust, in my opinion. However, there are plenty of people who will precribes these meds without even asking to see the actuall data.

Posted by: Neuropsych15 at March 24, 2009 11:33 AM

Celexa is a racemic mixture of two enantiomers (isomers which differ in the arrangement of bonds at one backbone carbon atom - the two isomers are mirror images of one another), one of which is Lexapro. The other apparently has no pharmaceutical benefit. When you take Celexa, you are taking Lexapro along with this inactive, mirror-image isomer which may lead to may only contribute to side effects. Because Lexapro is half of Celexa (the other half inert), one can make direct comparisons between the two.

Posted by: Tony at March 24, 2009 12:02 PM

"One of the big things I find appalling is that these approvals are based on 8 week trials with not one little hint about what happens after that."
Sara

I share the same feeling, Sara.

What happens after that becomes anecdotal and they don't care researching for these data.
Even when death is among one of the results.

Causa Mortis:
Anecdotal suicide
Anedoctal homicide

Just take a look at ssri.stories
Lots of anecdotal.

Posted by: Ana at March 24, 2009 01:52 PM

JC, I hear you loud and clear. I thought about responding to local doc but I am beginning to think it is pointless. These people distort everything and don't give a darn about listening. And we're the crazy folks?

Anyway, I was very moved by your post on Carlat's blog and wanted to let you know that.

Posted by: AA at March 24, 2009 03:14 PM

Yes JC, that comment of Carlat's sank his ship with me. Keep up the good work talking about your story JC--I hope you know you speak for my daughter when you do, and other kids. Why anyone would defend drugging preschoolers (or ignore that topic frankly) loses respect from me, that's all i can say.(esp when Biederman's drug trial of Risperdal on 4-6 yr olds is full of PROTOCOL BREACH and is being investigated by Grassley!)

Posted by: Stephany at March 25, 2009 03:59 AM

Dear JC:

Great post, Great commentary, and I could not agree with you more.

Yikes

Posted by: Yikes at March 25, 2009 09:21 AM

JC, a solution for Carlat and Biederman might be just to change the name of this phony dx to PIE-polar (throwing pies without parental permission). Or TRI-polar (involving both halves of your brain plus your nose). To me the most appalling thing is the FDA trashing its very own black box warning on SSRIs for those under 24. We know no one pays attention to the BB for seniors w/dementia (or other, surly or impudent seniors as was the case in that out-of-control CA Nsg. Home) but I guess the lesson here is - why EVER bother asking the FDA to place a black box if even IT doesn't follow its own little and way-too-late rule???......I like what I hear about the Texas initiative which, if it passes, will BAN atypicals for all children under the age of 11 without informed consent.

Posted by: anonymous at March 25, 2009 07:27 PM