OMG!!! That's What They Said! Significant


"Clinical studies of adults with depression showed that adding ABILIFY to an antidepressant helped to significantly improve depressive symptoms compared to adults treated with an antidepressant alone."

Okay, first let me say that this is not "Pick on Abilify Month."  I usually wander the web, (not quite so intentional as surfing), for interesting little tidbits to share with my readers.  But at my last appointment, my doctor gave me a list and told me to do my research and pick one.  So for the last month, I have had a focus.

Abilify has long since been eliminated as the winner of this assignment.  But it is such a good example of so many of my interests, including the use of language (as in this monthly OMG!! feature), marketing and clinical trials, that I can't let it go.  In fact, it gets another post later this month.  Not because I am picking on it, but because, well, stay tuned.

I found the winning quote for the month's OMG contest, "...helped to significantly improve depressive symptoms..." at Abilify.com.  It's the word "significant" that wins the award.  They really should share this award with many contestants, because that's what they all say, "significant."

The passage is found on the page intended for consumers.  So you would think they are speaking in the language that consumers speak.  This is not the case.  "Significant" in this sentence does not mean "significant" in the language that you and I speak.  The authors are referring to clinical trials, where the word "significant" is as significant as "toast," as in, "We are having toast for breakfast."  It is not significant enough to include as a facebook status update.  It is more like a twitter.  Though in FDA Land, it is the magic word, like "Open, Sesame", Sesame meaning big bucks.  So that is significant in the language that you and I do speak.  But I don't have a button for OMG Sesame!

At a University of Berkeley site, you can find the following definition:
Significance, Significance level, Statistical significance:  The significance level of an hypothesis test is the chance that the test erroneously rejects the null hypothesis when the null hypothesis is true.
 
And they wonder why we turn to Wikipedia? -- where it says:
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance.

So here is the deal.  Abilify.com is talking about their clinical trials, where people who were not responding to an SSRI or SNRI, one of the current crop of antidepressants, tried adding Abilify or placebo.  There are many interesting features about how Wyeth conducted these trials, and you will hear about them later.  The point is that they had to demonstrate to the FDA that those who took Abilify along with their antidepressant got better results than those who took the placebo.  If they could demonstrate that, the "effectiveness test," then they are part way toward approval for on-label usage, and a vast expansion of their market share, because there are a lot of us around who don't get better on the current crop of antidepressants, and more of us every day.  They also have to pass the "safety test" -- an issue for another day.

So how much better?  A "significant" amount.  And as I said, that does not mean what most people think it means, as in "I feel significantly better since I added Abilify to my treatment strategy."  Did you think that it did, when they said that "adding ABILIFY to an antidepressant helped to significantly improve depressive symptoms"?  It does not mean that at all.

So what does it mean?  There are several tests that researchers use to measure levels of depression.  One is the Montgomery Asberg Depression Rating Scale (MADRS).  This is a ten item scale that lets an evaluator rank your symptoms on a scale of 0 to 6, 0 meaning no symptoms, 6 meaning whale shit on the bottom of the ocean, to quote crazymeds.  Items include feelings of sadness, appearance of sadness, appetite, sleep, suicidal thoughts, etc.  Theoretically, you could get a total of 60 points, but that would put you out of the reach of clinical trials.  They don't let people that sick into clinical trials. They want to pass their clinical trials. So they go for a crowd that is easier to impress.

There were three clinical trials done for Abilify.  The results were consistent from one to the other.  So I will use just one as an example, the third, published in April, 2009.  172 people took a placebo along with their antidepressant.  They had a range of MADRS scores, and the middle score (the "mean") was 27.1, which is moderately depressed.  177 took Abilify with their antidepressant.  They also had a range of MADRS scores, with the middle score of 26.6, also moderately depressed.  There are a variety of small differences between these two groups.  In each case, those receiving the placebo were a lttle bit sicker, but as far as I know, not "significantly" sicker.  After six weeks, both groups had lower MADRS scores, meaning that both had reduced their depressive symptoms.  That is good news for both groups, from the patient's perspective.

Since the placebo group improved as well as the Abilify group, you could infer that some of the improvement came from the experience of being in a clinical trial itself, or maybe just from the passage of time, because people with depression do get better.  But the $64,000 question for Wyeth is whether there was a "significant" difference between the two.  And the answer -- ding,ding,ding -- is yes.  The placebo group reduced its score by 6.4 points, and the Abilify group by 10.1.  So the difference between the two was 3.7.  In the language of statistics, the probability that this difference of 3.7 points was due to chance is .1% -- one in a thousand.  If you get that score for two clinical trials, that's good enough for the FDA.  And they got it for three.

So isn't that significant?  Yes, if you are a statistician.  If you are a patient, if you are weighing the risks and benefits, then maybe yes, maybe not so much.  In a test with a possible score of 60, the difference between the two groups was less than four, or two questions that were answered just a little differently.  3.7 points on the MADRS scale means going from "looks miserable all of the time" to "appears sad and unhappy most of the time," and from "slightly reduced appetite" to "normal appetite."  Do you consider those two differences to be significant?  Is that what you expected when you read Abilify.com, "adding ABILIFY to an antidepressant helped to significantly improve depressive symptoms"?

I have clinpsych.blogspot.com to thank for helping me find the original research report.  In the next stage of the Abilify story, I will explore why these results, significant or not, did NOT impress the people who actually took the medication. 

The Chemistry Experiment -- Placebo

Wouldn't you know.  I take a few days off before my placebo post, and wired.com scoops me with Placebos are Getting More Effective.  Drug Makers are Desperate to Know Why, by Steve Silberman 08.24.09.  Well, Steve put a lot more into his article than I intended for mine.  It makes for a fascinating read, about the history and current study of the placebo effect, beginning with its discovery during World War II, when an Army nurse lied to a soldier in pain.  They were out of morphine.  So she told him the injection of saline solution was a potent new pain killer.  And the patient's pain was relieved.  

That story is the essence of the placebo effect.  "When referring to medicines, placebo is a preparation which is pharmacologically inert but which may have a therapeutical effect based solely on the power of suggestion." -- thefreedictionary.com.  

In 1962, the Food, Drug and Cosmetic Act began to require that medications prove their safety and effectiveness against placebos.  One group takes the medication.  Another group takes a placebo, or "sugar pill."  Their rates of improvement and side effects are then compared, to find out whether the medication itself causes the healing, or something else does, like the belief  in the medication, which marshals the body's own healing powers.  

Fast forward to the last decade, when more and more antidepressants have "failed trials," meaning that they perform no better, or not much better than the little sugar pills.  It seems that the new neurological medications are performing just as well as the old ones.  (I think this usually means that within 8-12 weeks, about 30% of people who take them improve their scores on various questionnaires that measure levels of depression.)  But oddly, over time, the placebos are performing better.  Which means the bar that the new meds have to cross to get approved is getting higher.

The Chemistry Experiment -- Augmentation

When I began The Chemistry Experiment, there were about twenty options out there for me to try.  I was a wuss and quit at six.  I said "no" to a fifth SSRI/SNRI, and rejected the whole class of MAOIs (Monoamine Oxidase Inhibitors) -- which were just too tempting to use as a backup plan.  Instead I headed east, and Chinese herbs got me through almost two years.  Later I returned to an antidepressant that hadn't been effective before, but at least it did no harm.  This time it helped.  Was this because I was taking Xiao Yao San as well?  Who knows.  But now it doesn't work any more anyway.

Meanwhile, there is a new strategy called augmentation.  If one med doesn't work, try combining two, an antidepressant with an anti-psychotic, anti-convulsant, mood stabilizer, atypical anti-psychotic.  Suddenly the number of possibilities is up to forty.  That doesn't actually give you 1600 potential combinations, because if you combine MAOIs with most of the others, it'll kill you.  Most days, that doesn't seem like a good thing. Anyway, the number of potential trials has increased exponentially, and I am nowhere near the end of the chemistry experiment.

The Chemistry Experiment -- The Cure

I saw a movie in 1995, The Cure. It was about two boys, eleven year old Dexter and Eric, a little older. When Eric learns that Dexter has AIDS, he decides to find a cure. People find cures all the time in unexpected places. Since Dexter is not allowed to eat candy, Eric thinks that might be why he has AIDS. Keeping track of Dexter's temperature in a notebook, the boys try a lot of candy. After the first trial results were in, finding low efficacy and an unwanted side effect of stomach ache, they switch to plants down by the river, making a series of infusions (tea). This time a stomach ache leads to a hospitalization. When Dexter's mother ends the experiment and Eric's mother tries to end the relationship, the boys head south on a raft to New Orleans, where there will be new plants.

The Ch
emistry Experiment was something like The Cure, only my doctors didn't monitor as closely as Eric, nor respond as quickly to my side effects. Part way through it, I drew this picture of The Chemistry Experiment. The bottles crossed off were of Prozac, Celexa, Remeron, and Nortriptyline. Cymbalta is the one being added to the test tube, which was my body. I was willing to try no more than three per series, insisting that I wash out the test tube between. I also changed psychiatrists after three, and quit entirely for a while after Effexor.

I saved all my unfinished scrips.
The pills fascinated me. They were the evidence of the violence to my body with which I was collaborating. My therapist really wanted me to throw them away. Eventually I did. But now I wish I still had them. Not to take all at once, that's not my plan. Just for evidence.

Skunk!

I have found a new blog to follow, Knowledge is Necessity: Musings on Mental Health by John McManamy. I think we are up to similar enterprises. John also has another website, McMan's Depression and Bipolar Web, which is to mood disorders what Jerod Poore's Crazy Meds is to neurological pharmaceuticals. Read the blog for musings, the others for information.

Meanwhile, here is the link to "Skunk," John's blow by blow of an encounter between the amygdalas of two mammals, a lesson in the amygdala that is more artful than Mother Amygdala from this blog, July 28, 2009. An added feature is the lesson in how to address the presence of this particular mammal in your house. Enjoy!

And thanks to John for his work.

Depression and the Nobel Prize

It was an irresistible title. I followed the link to the New York Times and found the October 21, 2008 story by Tara Parker-Pope, about Dr. Douglas C. Prasher, a biochemist whose early work contributed to what would later lead to a Nobel Prize -- for somebody else.

Prasher has recurrent major depressive disorder. Today he drives a courtesy van for a car dealer. He says there was more to his departure from science besides his depression, lack of funding, family obligations... But that is part of the story. Depression doesn't help you find funding and meet family obligations. Depression can turn tying your shoes into a challenge. Parker-Pope wrote, "I find Dr. Prasher’s story to be a notable reminder of the toll depression can take on the lives and careers of many brilliant minds."

I told the story to Helen this afternoon, ending in my most dramatic mode, "I coulda had a Nobel Prize!" She didn't let me laugh it off, "Well, you coulda had a PhD. You coulda been bishop of... or rector of..."

Crazy Meds

"You have to weigh the costs and benefits," the doctor said, her pen poised over the prescription pad. It sounds logical, doesn't it? And how interesting, that the doctor wants you to take responsibility for this major decision about your own health care, even when you are a mental patient.

Many trips to the doctor, many prescriptions later, I figured out what was wrong with that sentence. Let me put it this way: the cost of a Powerball ticket is $1; the potential benefit this week is $84,000,000. Wow. So millions of people weigh the costs and benefits and then buy their Powerball tickets twice a week. And the report out this week in the New York Times is that in 2005, ten out of every hundred Americans were on antidepressants, an estimated 27,000,000 people. I was one of them. It was logical.

Get it? There is a missing piece of information. What are the odds? Powerball tells you quite frankly. The pharmaceutical companies, not so much.

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