FDA: No link between Singulair and suicidal behavior

On Tuesday, the FDA announced that an investigation into Merck’s clinical trial data did not discover a link between Singulair (montelukast) and suicidal behavior. The investigation, which began 9 months ago, was prompted by a number of reported suicides, especially that of 15-year-old Cody Miller who took the drug and appeared to have no history of mood or behavioral problems. (It is worth noting here that Singulair “is the top-selling drug for people under 17 years old” and Merck’s biggest seller with annual sales of close to $4.5 billion.)

In attempt to assess Merck’s data better, the FDA also investigated AstraZeneca’s Accolate (zafirlukast) and Cornerstone Therapeutics’s Zyflo (zileuton). Although the FDA did imply that “the data were inadequate to draw a firm conclusion” and said that the clinical trials were not set up to observe any psychiatric behavior. Here are the data the FDA discovered during their review of these trials:

Singulair: 41 placebo-controlled trials that included 9,929 patients

• Reports of suicidal thoughts: 1 (treated with Singulair)
• Attempted suicides: None reported
• Completed suicides: None reported

Accolate: 45 placebo-controlled trials that included 7,540 patients

• Reports of suicidal thoughts: 1 (placebo group)
• Attempted suicides: 1 (placebo group)
• Completed suicides: None reported

Zyflo: 11 placebo-controlled trials (number of patients unknown)

• Reports of suicidal thoughts: None reported
• Attempted suicides: None reported
• Completed suicides: None reported

Forgive me for being cynical but the data sounds fishy. I can’t pinpoint why but it does. The suicide numbers and patient involvement data seem to deviate some from the numbers listed in Merck’s PR issued last March. (I’m seeing 11,000+ patients vs. 9,929 patients.) Regardless of the clinical trial data, it appears that the FDA as of yet have not reviewed post-marketing data.

Scott Korn, a senior safety surveillance executive for Merck said in an article for Reuters:

“‘At the time we did not believe, and we still don’t think a link has been established’ between Singulair and the suicides.”

In the same article, Sanford Berstein analyst Tim Anderson had this to say about the possibility of the FDA finding a link:

“If the… safety review leads to a stern warning about behavioral changes in the Singulair label, this could frighten users of the drug or their parents and give Merck’s competitors ammunition to attack the brand.”

The Washington Post has Dr. David Weldon, director of the Allergy and Pulmonary Lab Services at Scott & White in College Station, Texas, on record saying that he had not “seen any increase in psychiatric problems with the drug but that some patients had complained of nightmares after starting on Singulair.” (Note: It appears that the closest conflict of interest Weldon would have here is that he served as a consultant and is honoraria for AstraZeneca.)

Dr. Rauno Joks, head of the SUNY Downstate division of allergy and immunology, made an interesting point in the Washington Post article:

“The physician really needs to review whether there are symptoms that have developed since patients started taking the medication, if there’s an underlying depression that was there before medication started.

Also, seasonal allergies in and of themselves can cause fatigue and lethargy, which makes it harder to assess, because those are some of the symptoms you have with depression.”

The FDA says they’ve completed analyses of submitted clinical trial data but their “safety review will continue” for several more months before they come to a concrete conclusion. For customer testimonials, check out medications.com that has over 2,300 people reporting side effects and askapatient.com that has an average 2.3 rating from 524 reviewers. The most commonly reported mood-related side effect on both of the sites is irritability.

John Grohol interviews Wyeth's VP of Medical Affairs on Pristiq

Dr. Grohol interviewed Dr. Phil Ninan, Wyeth’s VP of Medical Affairs on Pristiq, its efficacy, and surrounding issues. It was quite an interesting interview (and long) but here are some highlights that I chose to comment on. I’ll be making some comments in between Dr. Ninan’s answers due to the extensive length. Some parts of the answers have been truncated.

Great editorial in NYTimes

The New York Times published a great editorial supporting a ban on much of the lavish treatment that doctors get from drug reps. If adopted by medical schools, restrictions would include:

• Ban on personal gifts, industry-supplied foods and meals, free travel (not reimbursed for services), and payment for attending industry-sponsored meetings
• Ban on ghostwriting, the practice of drug companies drafting an article and then getting a doc to slap his or her name on it making it look at though the doc actually wrote it
• Drug samples would have to be submitted to a central pharmacy not individual doctors

The restrictions, however, end there. The editorial says the proposal goes far but not far enough.

Patients need to be assured that their doctors are prescribing what’s best for them, not what’s best for companies.

Can someone get a doctor to read this?

Wyeth Pushing Pristiq Hard

The Wall Street Journal reports that Wyeth, desperate to make money off of its Effexor XR-knockoff, Pristiq, says it will slash the antidepressant at a 20% discount compared to Effexor’s price. The price slash, CNN money reports, is a result of less-than-impressive clinical trial data on Pristiq’s “safety and effectiveness.”

Wyeth SVP Joe Mahady told analysts that Pristiq will sell for a flat $3.41 per tablet for both mid- and high-dose, Dow Jones Newswires’ Peter Loftus reports.

Wyeth, apparently, has done this in the past. Back when it was known as American Home Products, the company slashed its price on Protonix, its heartburn drug, to compete with AstraZeneca’s Prilosec. The drug generated $1.9 billion in profits for Wyeth last year. CNN Money reports that Teva Pharmaceuticals and Sun Pharmaceuticals began selling the generic version of the drug and handily cut into Wyeth’s profits: the company reported a 4.6% decline in profit and a 66% drop in sales for the drug for the first-quarter. What will happen with Pristiq remains to be seen. I’m not sure that doctors in 2010 will want to dole out prescriptions for Pristiq when they can save patients—and insurance companies—money by prescribing what will then be known as venlafaxine. WSJ also notes:

A month’s supply of sertraline (Pfizer’s old hit Zoloft) or fluoxetine (Lilly’s Prozac) goes for 50 cents a day at drugstore.com.

$3.41 or $0.50 per tablet. It wouldn’t surprise me if some insurance companies choose to exclude Pristiq from its list of covered drugs. Regardless, Wyeth expects sales of the drug to exceed $1 billion in its first year.

The drug will hit the shelves in May.

NYTimes

“The drugs save lives, and we often have no choice but to use them — even if we have questions about their long-term use. But the questions are big ones, and we owe it to our patients to try to answer them.”

Dr. Richard Friedman, a frequent mental health columnist for the New York Times, has written a piece that questions the use of antidepressants and how dependent patients have become on them. I’ve read Friedman’s previous columns and appreciate his realistic take on the psychiatric and psychological field. His most recent piece is worth reading.

Brief update on Singulair-suicide link

Merck issued a press release today responding to the FDA’s investigation. Along with the standard "we didn’t know about this problem until after it the market" disclaimer, the PR mentioned:

In a cumulative analysis recently provided to the FDA of Merck’s randomized, double-blind, placebo-controlled clinical trials, which included over 11,000 adults and children in over 40 studies who were treated with SINGULAIR, there were no reports of suicidal thoughts or actions and no completed suicides in the patients who received SINGULAIR.

Additionally, in a cumulative analysis recently provided to the FDA of Merck’s randomized, double-blind, clinical trials that compared SINGULAIR with other active agents to treat asthma (which included over 3,900 adults and children who were treated with SINGULAIR and over 3,400 who were treated with other asthma therapies), there was 1 patient who attempted suicide who received SINGULAIR, and there were 3 patients who attempted suicide who received other asthma therapies (including inhaled corticosteroids and long-acting beta-agonists).  These studies were not designed to compare the rate of suicide in patients taking SINGULAIR with the rate of suicide in patients taking these other asthma agents.

Did Merck report that one suicidal attempt when compared to "other active agents to treat asthma"? It doesn’t say anything in their patient safety or prescribing information when I checked. Perhaps someone can find out whether they reported this in their clinical trials?

In the meantime, the Singulair section of medications.com is ablaze with parents who are now expressing concern over their children’s well-being on the drug. Apparently, issues have cropped up with the drug even before the FDA announced their investigation.

Pristiq receives approval from FDA

More than a year ago, I promised to keep tabs on Wyeth’s new (renamed, rather) drug Pristiq. So I’m living up to it.

On February 29, 2008, the FDA granted Wyeth approval to move forward with putting the drug out on the market.

Wyeth said the company planned a big sales effort to introduce the product to psychiatrists and primary care doctors.

There’s a problem with that sentence. I’ll give you a second to figure out what’s wrong with it. Haven’t got it yet?

Primary care doctors. PCP should not be in the business of prescribing or providing psych meds. I’ve gone on and on about it at length before, but I’ll mention it again. PCPs are trained to treat overall conditions that have no need of referral to specialists. Think about it this way: If your psychiatrist prescribed anti-inflammatory medication because you mentioned that you’ve been having problems with your foot, you’d be taken aback, right? If a dermatologist prescribed heartburn medication after a patient mentioned he’d been having heartburn trouble, that would seem almost illogical, wouldn’t it?

(Pristiq logo from Pristiq.com)

The Zoloft-rage/violence connection

[This post is quite lengthy so I suggest you grab a cup of coffee or tea and sit down and read it. The following is not for the faint of heart (or those with a lack of time).]

It’s been amazing to me that I’ve received numerous comments on Zoloft inducing rage. I’m humbled by having a Pittman supporter visit my site and post some comments from the ChristopherPittman.org forums. Read the following:

In my senior year in high school I was diagnosed as being severely depressed and put on medication. The first medication that I was on I took for 5 months and it made me really aggressive. My friends and family noticed the change and I told my doctor about it and she changed my meds. After that I was fine. I am normally a very passive person and will let just about anything fly. But the medication made me really aggravated and aggressive toward my friends and family and it seemed that I wasn’t overcoming my depression. I just got done watching the 48 hours investigation on the Discovery Times Channel and felt a connection with Chris. I felt that I had to write this to let you know that Chris is not the only one out there that had these side effects. I think there should be a study done to see how many people that take antidepressants have increased aggression. The problem is that the pharmaceutical industry has deep pockets and many lobbyists. I hope this helps in some way.

And another:

I remember the case when it happened.

At the time I thought, “Zoloft right”.

Let me tell you my physician put me on Zoloft and it took about three weeks for my to become psychotic and I’m a 50 year old woman.

I have three children and I don’t make a lot of money but please let me know if I can do anything for the Pittman boy.

The jury should have been placed on Zoloft before they made they decision. Unless you’ve experience it you simply cannot believe its’ effect.

I did a bit of quick reading/research into Zoloft triggering violence in people who otherwise would have never been violent and it seems that are a few stories out there to support the assertion. I found a few comments on depressionblog.com that mentioned a link between Zoloft and rage fits. A Salon.com article published a story antidepressants inducing rage in 1999. Apparently, Brynn Hartman, the wife of famous comedian Phil Hartman, killed herself and her husband while taking Zoloft. While close friends attribute the sudden behavior on the antidepressant, others attribute it to a combination of the medication with cocaine and alcohol in her system. (Zoloft does have a warning against alcohol use in conjunction with the drug.)

One interesting thing I learned from the article is that this kind of behavior is often labeled under the name akathisia on patient safety guides. Most – if not all – of the major antidepressants list akathisia as a side effect. Here’s the initial description of this condition from Wikipedia:

Akathisia, or acathisia, is an unpleasant subjective sensation of “inner” restlessness that manifests itself with an inability to sit still or remain motionless… Its most common cause is as a side effect of medications, mainly neuroleptic antipsychotics especially the phenothiazines (such as perphenazine and chlorpromazine), thioxanthenes (such as flupenthixol and zuclopenthixol) and butyrophenones (such as haloperidol (Haldol)), and rarely, antidepressants.

Akathisia may range in intensity from a mild sense of disquiet or anxiety (which may be easily overlooked) to a total inability to sit still, accompanied by overwhelming anxiety, malaise, and severe dysphoria (manifesting as an almost indescribable sense of terror and doom).

No real mention of extreme anger or irritability mentioned there. But if you read on…

The 2006 U.K. study by Healy, Herxheimer, and Menkes observed that akathisia is often miscoded in antidepressant clinical trials as “agitation, emotional lability, and hyperkinesis (overactivity)”. The study further points out that misdiagnosis of akathisia as simple motor restlessness occurs, but that this is more properly classed as dyskinesia. Healy, et. al., further show links between antidepressant-induced akathisia and violence, including suicide, as akathisia can “exacerbate psychopathology.” The study goes on to state that there is extensive clinical evidence correlating akathisia with SSRI use, showing that approximately ten times as many patients on SSRIs as those on placebos showed symptoms severe enough to drop out of a trial (5.0% compared to 0.5%).

Empathetic therapists

Read a good op-ed in New York Times on whether therapists need to have shared experiences with their patients to be a good therapist.

Article Analysis – “Breaking it down: Mental health and the African community”

Liz Spikol linked to this article back in December and as a Black American with West Indian heritage (and by default, African and French), I couldn’t resist commenting.

Author Morenike Fasuyi blasts the United Kingdom’s mental health system as being less than inadequate for Africans. I don’t doubt it.

I do wonder about Fasuyi’s seemingly sheer hatred for anyone of European descent (in America, we’d refer to them as “white” or “Caucasian”). The article seethes with anger.

“The general consensus suggests that African people have to work twice as hard as their european counterparts in every aspect of our social, cultural and economical existence in order to make ends meet.”

This also is the case for Black Americans.

Fasuyi explains how she’s been diagnosed with bipolar disorder but says her disorder is mainly triggered by things related to Africa: “slavery, politics, oppression.” Her turning point was on May 1, 2004 when “it was as if [her] ancestors called” upon her and “removed the scales from her eyes.” She refers to Karl Marx when speaking about “groups” – Africans – who are oppressed and eventually rise up and lead a revolution. In addition, she believes the numbers 7 and 9 relate to the African people and that 2007 could be the year when “division within the African community” would be “homogenized[d]… to effect change.”

As a Black American, I know that African people truly value their ancestors and even practice ancestry worship. This is where I believe she is coming from. To any other nationality, Fasuyi is crazy (no pun intended). It wouldn’t surprise me if her mental health status file read, “bipolar disorder with psychosis.” Not knowing about African ancestry worship can make any doctor of non-African nationality misdiagnose Fasuyi. To be able to accurately help her, she must be accurately understood.

She asked for an African psychiatrist who might have a cultural understanding of where she was coming from. She mentions this was a slow process since “there [were] hardly any.” She also asked for an African social worker but was given “an insensitive male european (sic) social worker who adversely affected my health with his actions, racist remarks and incompetence.”

She takes a nice jab at Big Pharma and pharma reps, too:

“Maintaining you within the system keeps consultants in their jobs and increases the profit of the pharmaceutical industry, which has a turnover of billions.”

Zyprexa; Cymbalta, anyone?