the system…

Posted on Thursday 8 September 2011

Drug development for anxiety disorders: new roles for atypical antipsychotics
by Carson WH, Kitagawa H, Nemeroff CB
Psychopharmacology Bulletin 2004;38 Suppl 1:38-45.

Source: Global Product Development/Aripiprazole, Princeton Aripiprazole Unit, Otsuka America Pharmaceutical, Inc., in Princeton, NJ.
Abstract: Anxiety disorders are prevalent and frequently comorbid with depression. Rates of response and remission for anxiety disorders are low despite marked improvements in treatment in the past several decades. Antidepressants and anxiolytics remain the most frequently prescribed agents for anxiety disorders, but the numbers of prescriptions for novel forms of therapy, such as anticonvulsants and atypical antipsychotics are increasing. For the atypical antipsychotics, agonist activity at the 5-HT(1A) receptor has been hypothesized to translate into anxiolytic effects. A small, but growing, literature suggests that atypical antipsychotics are useful as augmentation therapy for treatment of refractory anxiety disorders. The next generation antipsychotic, aripiprazole, has a unique mechanism of action (ie, combined D(2) and 5-HT(1A) partial agonist and 5-HT(2A) antagonist) and improves depressive and depressive/anxiety symptoms in patients with schizophrenia. Further studies examining the effect of aripiprazole and other atypical antipsychotic drugs on depressive and anxiety symptoms in patients with refractory anxiety disorders are warranted.
2004 was something like a peak year for articles like this. Not long after that in 2006, Dr. Nemeroff stepped down as editor of Neuropsychopharmacology, the Journal of the American College of Neuropsychopharmacology [ACNP Journal Editor Quits Amid Exposure of Conflicts of Interest]. And then came 2008 and an even bigger fall [Under Grassley’s Glare, Emory’s Nemeroff Gives Up Psychiatry Chair]. Now we read this:
Antipsychotics Increasingly Prescribed for Anxiety
Psychiatric News
by Jonathan Wolfe
September 2, 2011

Researchers find a significant rise in antipsychotic prescriptions for patients diagnosed with anxiety disorders, despite limited studies on safety and efficacy of the medications for these disorders. Antipsychotic medications that have been approved for use in treating serious mental illnesses such as schizophrenia and bipolar disorder are increasingly being prescribed by office-based psychiatrists in an off-label use for patients with a range of common anxiety disorders…

“The dramatic increase in atypical antipsychotic use in anxiety disorders in the absence of FDA approval for these indications is surprising in view of the many medications for which there is both evidence of efficacy and FDA approval,” said Charles Nemeroff, M.D., Ph.D., chair of the Department of Psychiatry and Behavioral Sciences at the University of Miami’s Miller School of Medicine. “Considering the significant side-effect burden of atypical antipsychotics, and their cost, decisions of their use for non-FDA-approved indications, including anxiety disorders, should be made with careful risk-benefit evaluations.”
A change of heart? Redemption and reparation? Or perhaps homage to the reflections of Prince Don Fabrizio Salina in Lampedusa’s The Leopard:

If we want things to stay as they are, things will have to change.

And to push this metaphor a bit beyond its bounds, "Can the leopard change his spots?"

I expect that most of us would say "no" given Dr. Nemeroff’s track record. But there is another question embedded in this little vignette. Why is Johnathan Wolfe enlisting Dr. Nemeroff, of all the people, to comment on this particular article? One can only assume that someone at the American Psychiatric Association is trying to help Charlie Nemeroff stay in the game. That certainly seemed to be the case when NIMH Director Tom Insel intervened on Nemeroff’s behalf in getting his chairmanship in Miami [the Nemeroff Defense].

And there really is no paradox here after all. The first article [2004] is an ad for using Aripiprazole [Abilify] for anxiety financed by the manufacturer [I think of such publications as "on call" articles]. Otsuka America Pharmaceutical called and Charlie signed on. The APA’s Psychiatry On-Line [2011] called and Charlie signed on. No difference really – expertise for hire.

Then there’s the content of Charlie’s response – "… surprising in view of the many medications for which there is both evidence of efficacy and FDA approval." In the psycho-pharmaceutical game, the FDA is a board piece with lots of moves. On the one hand, using a psychopharmacologic agent "off-label" is novel or innovative [as in the 2004 article] – life on the leading edge. On the other hand, FDA approval, once granted, is seen as a stamp of approval and the drug becomes the gold standard for treatment. All FDA approval really means in that the drug was statistically better than nothing in a short term [usually industry-funded] clinical trial. For example:

As a matter of fact, this Seroquel XR ad was the heading for the page with the Psychiatric News article quoted above. Certainly, AstraZeneca has been a poster child for off-label marketing:
AstraZeneca settles Seroquel off-label suit for $520m, CIA
Medical Marketing & Media
by Matthew Arnold
April 27, 2010

AstraZeneca agreed to pay $520 million and enter a five-year Corporate Integrity Agreement to settle a federal case against the company for off-label marketing of Seroquel, the Departments of Justice and Health and Human Services’ Healthcare Enforcement Action Team announced…
Now we are bombarded constantly with this ad for Seroquel XR in Major Depressive Disorder. Seroquel is soon to go off-patent, so AstraZeneca came out with Seroquel XR as a patent extender. Then they got FDA Approval for Seroquel XR as an add-on in Major Depressive Disorder. Thus the ads. And notice the small print:
    * for adult patients with an inadequate response after at least six weeks of treatment with an antidepressant.
As things have evolved over the last twenty-five years, the Key Opinion Leaders from academic psychiatry [KOL], the Pharmaceutical Industry [PHARMA], and the Food and Drug Administration [FDA] have done the dance I’m trying to describe here in countless permutations and combinations, but there’s another essential element – the psychiatric Diagnostic and Statistical Manual [DSM] itself.
Without the DSM in its current format, this dance becomes harder to bring off. The drugs are approved by the FDA for specific DSM Disorders, as if they are discrete diseases giving PHARMA a definable target for certification – as in the ad for Seroquel XR above. The DSM also gives the pharmaceutical industry another avenue into the process – a topic for a later post. But for the moment, I’ll stop this rambling set of associations to the Psychiatric News article by adding, unfortunately, another element to the system for further consideration:
I say "unfortunately" because one would hope that the National Institute of Mental Health [NIMH] would not be caught up in this tawdry dance. But when one reads Dr. Stahl’s recent comments [Are future psychiatric treatments doomed? Be careful what you ask for…you just might get it., Is the DSM-V Necessary?] and consider NIMH Director Tom Insel’s behavior during his time in that position, there’s really no choice but to add the NIMH to the circle:
    I am blogging today from Paris at the ECNP meeting, having attended the Royal Society of Medicine meeting outside of London last week to discuss the future of new drug development in psychiatry, paid by the taxpayers of the UK and charities, not Pharma. This meeting involved US colleagues Tom Insel (head of the National Institute of Mental Health), David Kupfer (head of DSM V rewrite), and several academic experts and industry executives from the US and the UK and was covered by the BBC and a report of it aired on UK television. I will report the results of our discussions of new drug development in another blog in a few days.
We kept our heads in the sand for twenty-five years and failed to note all that was happening around us. It’s time to wake up and, if anything, become hypervigilant to all possibile avenues for this dance continuing..

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