The Chemistry Experiment: Muppets Version

When your doctor, pen poised over prescription pad, tells you to weigh your costs and benefits, you will have next to no information with which to do so.  Over the last several and coming weeks, we are constructing an algorithm to help you comply with your doctor's instruction to make this calculation.  But remember, the best this algorithm can do is give you the odds.

After you calculate your odds, you may decide to proceed with this chemistry experiment and put the chemicals at issue inside your body, your own personal test tube.   At that point, you no longer have odds.  You have results.  Your doctor may not expect this, but once you have results, you will weigh your costs and benefits again.  You will make a new decision, this time with new information.

This is a good thing.  This is what people who conduct experiments do.  They use the information they have gained from one experiment to move on to the next.

This week's post is brought to you from the laboratory of Dr. Bunsen Honeydew, with the aid of his assistant Beaker. My thanks to Beaker in particular, for his contribution to science.

photo by Linda Bartlett, in public domain

OMGThat'sWhatTheySaid -- Noncompliance

Before I move to the costs side of Weighing the Costs and Benefits, I pause to consider the concept of noncompliance.

Noncompliance is not one of the best candidates for the OMG! Award, because I cannot point to specific usage -- it is ubiquitous.  On the other hand, it is precisely what this award is about, going to the heart of how language frames thought.  In this case, the word simultaneously names and creates a relationship between consumer and provider.

I don't particularly care for the terms consumer and provider when it comes to health care.  But I use them here, where they distinguish those who consume, literally put pills inside our mouths, from those who fill out those little slips of paper that provide the pills.  Providers replaces pushers, a term I used in a fit of pique last week.  This week, I have resolved to be more polite.

Consumers are told to weigh our costs and benefits.  When we comply with these instructions and, having done so, decide that the costs exceed the benefits, and therefore decide not to consume, then providers call us noncompliant.  What exactly is communicated here?

What is noncompliance, anyway?

I went to the dictionaries.

According to Webster's New World College Dictionary, noncompliant means failure to comply; refusal to yield, agree, etc.

MedicalNet.com puts it this way: Noncompliance: The failure or refusal to comply: the failure or refusal to conform and adapt one's actions to a rule or to necessity.

Don't you hate it when one word is defined by another word that still needs to be defined?  I went back to Webster's, and got these alternatives. 

COMPLIANCE

1: a -- the act or process of complying to a desire, demand, proposal or regimen, or to coercion; b -- conformity in fulfilling official requirements;

2 : a disposition to yield to others;

3 : the ability of an object to yield elastically when a force is applied.

So.  One has a desire, demand, proposal, regimen or official requirements, and may have access to force or coercion.  The other fails, refuses, or does not yield.  I wonder which is which? 

Scientists Study Noncompliance

Providers are disconcerted when consumers fail to consume, and spend a lot of time trying to figure out why.  By the way, this link goes to a review of literature by Alex J. Mitchell, a consultant and senior lecturer in liaison psychiatry at the Leicester Royal Infirmary in the United Kingdom, who receives no compensation from pharmaceutical companies.  I often link to reviews of literature.  Their authors read a jillion studies, including ones to which I do not have access.  Then they summarize the highlights of whatever consensus may have come from these studies.  Reviews of literature put a lot of information in one place.  Mitchell has 59 footnotes (okay, not a jillion -- I exaggerated), in case you want to look up the research behind a particular point.

So scientists speculate, do research, write articles, hold conferences and  train residents, all in efforts to increase compliance.  Their hypotheses about the causes of this behavior include inaccurate beliefs about medication, lack of insight into ones illness, lack of education in general, cognitive impairment, weight gain, sexual dysfunction, and poor patient/doctor relationship.

Mitchell even developed a flow chart to categorize the behaviors of patients: full, partial and excess adherence, intentional and unintentional non-adherence, for external or internal reasons, and various combinations of these.  Not telling your doctor that you have stopped taking your medication is called covert discontinuation, and in other places, covert noncompliance -- that word again, this time with the naughtiness of covert.

A friend noticed that Mitchell missed a category on his flow chart, the consumer who is compliant with other medications, but consistently, though inadvertently, forgets one particular medication that she thinks is the source of uncomfortable side effects.  That could be covert internal unintentional partial non-adherence.  Or would it be covert internal intentional partial non-adherence, covert here meaning that her intention is undisclosed to herself?  The flow chart matters, because having divided noncompliant consumers into subgroups, then they test different strategies to bring different subgroups back into compliance.

Some notice the non-PC nature of the word noncompliance.  While most articles I found use the term, occasionally, as in Mitchell, I come across non-adherence.  Non-adherence is supposed to imply a mutual agreement between two parties about what the treatment regimen will be.  Other articles use the terms interchangeably, recognizing a fig leaf for a fig leaf.  After all, presumably the consumer and the provider have agreed together about the regimen to which the consumer will adhere.  Only notice, if the consumer does not adhere, then he/she has violated an agreement, or broken a promise.  Still naughty.

Matthew Keene, who serves as an adviser or consultant to GlaxoSmithKline, Cephalon and Pfizer, might have merited the OMG Award on his own, for Confusion and Complaints: The True Cost of Noncompliance in Antidepressant Therapy.  But why pick on just him, because, like I said, this language and weltangshauung (as they say in philosophy -- it means world view) permeates the literature?

Why Don't Consumers Consume Their Antidepressants? -- What the Providers Say

Mitchell cites a study indicating that 10% of those prescribed antidepressants never show up at the pharmacy at all.  Keene's figures are that 28% quit within the first month, 50% within 60 days, and only 28% are still in compliance at six months.  Keene asks, Why do patients prematurely discontinue antidepressants, medications that may improve and perhaps even save their lives?  His answer -- one of the 3 C's of noncompliance: confusion, costs, and complaints. 

Confusion, costs and complaints.  Notice that each of these is patient-centered.  He didn't say incoherent, financially foolish and picky.  But they are implied in the rest of the article.  Notice also that he did not describe the phenomenon from the patients' perspective.  He could have said inadequate communication, ineffective or intolerable medications and inaccessible health care and still preserved his clever alliteration.

Why Don't Consumers Consume Their Antidepressants? -- What the Consumers Say

What if patients wrote these articles, or were even consulted?  Actually, they have been consulted.

44% consumers who discontinue medication before their providers would like (the research calls it prematurely) say they did so because it made them sick, most commonly nausea, headache, drowsiness, and increased anxiety.  Well, duh.

I don't know.  Has it occurred to anybody besides me that we could solve this puzzle and put all that research time and money to better use if we gave the scientists a turn as the lab rats?

Another 44% consumers report that they discontinue because the medication is not effective.

That leaves 16% unexplained.  I will get back to them when I discuss costs more thoroughly.

I sorted through lots of these studies before it finally occurred to me to compare rates and reasons.  Noncompliance at six months is 72%.  Back to NIMH's STAR*D study, when trial subjects received compensation, free medical care, extensive information and regular support, antidepressants were ineffective for 50% of those who took them and intolerable for 16%, a total of 66%. -- That was the first trial.  By the third trial, medications were ineffective for 83% and intolerable for 26%, more even than the total.

What I want to know is just how many people take antidepressants when they make them sick and/or don't work anyway?  I personally know three.  Consistent with research findings, that better educated consumers are more compliant, these three have among them a BA, a Masters and a PhD.

Is there something going on here that is not about good medicine?

Rethinking Consumer Noncompliance

Psychiatrist Allan Showalter, Rethinking Patient Noncompliance, challenges the premises behind repeated and repeated research on noncompliance, a behavior which found across other diagnoses, not to mention life issues ranging from flossing to portfolio diversification, as well.  Here is the video of an Iowa Hawkeye football player on a motorcycle, one week before the game with our biggest rival.  A football player.  No helmet.  Despite repeated pleas of Kirk Ferentz, the Hawkeye coach.

I do recommend that you follow Showater's link for the novelty of his thinking.  One example: Nothing in [the definition of noncompliance] implies a moral obligation on the part of the patient to follow those recommendations or to the clinician who makes those recommendations to enforce them.

Countertransference

Yuval Melamed and Henri Szor, The Therapist and the Patient: Coping With Noncompliance, focus on the relationship between the patient and therapist as the source of noncompliance, rather than taking patients at their word.  On the other hand, they use a word that I did not find in any other article.

Countertransference.  Okay, ignoring the definition that includes the word transference, [again -- so irritating when dictionaries do that], Webster's defines countertransference as the complex feelings of the psychotherapist toward the patient.

Melamed and Szor think that noncompliance arouses reactions in therapists who feel that this behavior exemplifies a lack of trust in them and in the corpus of knowledge they represent.  I think that takes us part way there.

It is the therapist's job to manage the dynamics of countertransference in what is an unequal power relationship. That management would include not allowing the therapist's feelings toward the patient to misinterpret the patient's experience as hostility and thus misdirect the intervention.

I have not found evidence that providers of medication ever explore the impact of their own feelings on their treatment of consumers, at least in the arena of noncompliance.  Countertransference is a regular part of psychotherapists' training.  If it is ever mentioned in medical school, none of the literature gives evidence that the lesson sticks.

Weighing the Costs and Benefits -- Progress Report

Sorry about all the numbers in this post.  I have not found in the research any effort to measure the costs side of you have to weigh the costs and benefits that is not filtered through the concept of noncompliance.  So the algorithm will suffer from research that is compromised by its initial assumptions.  Thta is why we had to start with the OMG Award.

Next week, the Muppets will give us a break, while my brain does a bunch of number crunching.

drawing of dictionary in public domain

Adam and Eve by Albrecht Durer, in public domain

photo of Warren G. Harding in public domain

photo of woman pointing taken by David Shankbone,

used by permission under the Creative Commons 

Attribution-Share Alike 3.0 Unported licence and modified

remainder flair from facebook

Weighing Costs and Benefits Part II: Benefits

Today the Free Range Lab Rat, yours truly, continues my extended series on the Chemistry Experiment, that effort to find the chemicals that will make a dent in the suffering of those with mood disorders.

I asked, Will it work for me?

And the doctor answered, We won't know until you try it. 

THAT is the Chemistry Experiment. 

So three weeks ago I published my

Manifesto

If I am a lab rat, I will be a free-range lab rat.

Because I am a free-range rat, I decide which experiments I am willing to try.

Of course I do.  The doctor expects me to decide.  Why else did she say,

You have to weigh the costs and benefits. 

Only -- there is no scale.  Which led me, two weeks ago to continue my manifesto.

I now insist that I contribute more to this enterprise than my body.

So I have decided to create the scale.  I call it an Algorithm.  Algorithm is science-speak for a set of logical rules applied to objective data to solve a problem.  The problem to be solved is 

Do I Want To Put These Chemicals Inside My Body?

It turns out there are lots and lots of these costs and benefits to weigh.  The numbers you get in your fifteen minute med check are abbreviated and oversimplified to the point of useless.  So this is going to take a few weeks.  I am breaking it down, one step at a time.  Like I said, a set of logical rules applied to objective data to solve a problem.  I promise as few numbers and as many pictures as possible.  Plus another musical interlude.

Two weeks ago, I made a list of factors, all the things that go into the scale.  Today we look at the good side, what the doctor calls BENEFITS.

Here goes. 

Effectiveness Rate

Tribute to Survival

This is dedicated to those who are surviving the Chemistry Experiment, and to those who hang in there with us.

Bring your courage and your hope, whatever you can manage.

And your helmet.



Thanks to Danny MacAskill and Band of Horses.

Weighing the Costs and Benefits Part I -- What Counts?

Manifesto

If I am a lab rat, I will be a free-range lab rat.

There.  I feel better already.

To recap from last week:

You Have to Weigh The Costs and Benefits

That is what the doctor says.

Last week I promised I would develop a way to do that.  So this week we play math games.  For the next few weeks, actually.

Now, don't freak out.  I am not going to ask you to do math.  I am going to make up some rules.  You are along for the ride.  Though do feel free to suggest better rules.  Plus, I promise lots of pictures.  And a musical interlude.

I am a rat.  I live in a laboratory, where I participate in the Chemistry Experiment.  Along with other scientists, I am trying to find the chemicals that will make a dent in my mood disorder.  Not theirs.  Mine.  Which is how I got the rat end of this job.  But because I am a free-range rat, I get to decide which experiments I am willing to try.

I now insist that I contribute more to this enterprise than my body.

Manifesto of a Lab Rat -- Weighing the Costs and Benefits Part I

I Am A Lab Rat.  Yes, I am.

Here is the deal.  I was lucky enough, and you were lucky enough to be born after the discovery of penicillin (1928).  Well, I don't know when you were born.  But evidently penicillin was discovered before it became a life or death issue for either of us, or I wouldn't be writing and/or you wouldn't be reading Prozac Monologues.  This is good.

In another age, my ruptured appendix might have been treated with leeches.  That would not have been good.

As far as my more immediate health challenge goes, we are barely out of the leech stage.  Okay, that's a bummer, the timing of my life, that is.  But like I said, ruptured appendix, penicillin.  It could have been worse.

Research Into Mental Illness -- Rats

In the treatment of mental illness, they have figured out that leeches don't work.  They think chemicals might. They just haven't figured out which ones.  They are working on it.  They have lab rats, rattus norvegicus to be specific, who do the heavy lifting in this Chemistry Experiment.  Some people question the ethics of what gets done to these poor rattus norvegicuses who participate with not a single informed consent form in sight.  But that not only is another post, it is another blog.

DSM 5 and Mood Disorders, Part I -- What's at Stake

Earlier this month, the American Psychiatric Association released the long awaited proposed revision of their Diagnostic and Statistical Manual of Mental Disorders (DSM-5).  It is available now for public comment, with an anticipated publication date for the final version in May 2013.  To call this the Bible of Mental Illness is to overestimate the significance of the Bible.


The DSM was first written to give clinicians and researchers a common vocabulary and a common understanding of the various diagnoses of mental illness.  John McManamy has related this history on his blog Knowledge is Necessity.  I refer you to his thorough account, found in the links at the bottom of his post. -- [Hey, John -- I recognized your image for "Few Surprises."  It was one that I considered for this post!]

The way the DSM works always reminds me of a Chinese menu.  For example, if you have one symptom from Column A and at least five from columns A and B, for over two weeks, you have Major Depressive Disorder.  You can upgrade your core diagnosis with specials offered alongside the basic menu.  These lists of symptoms provide a common vocabulary and simplify diagnosis, so that family practitioners commonly diagnose depression and prescribe antidepressants, without referral to psychiatrists.  This practice provides a boon to the pharmaceutical industry, which markets heavily to family practitioners.  If patients had to see a psychiatrist to get a prescription, fewer people would take antidepressants, since there is greater stigma attached to treatment by a psychiatrist, psychiatrists are in short supply in many parts of the country anyway, and health insurance plans provide inadequate coverage for psychiatric care. So family practitioners prescribing for depression sells more antidepressants.  Big Pharma wants to keep the DSM simple.

Over time, even as therapists have become more eclectic in their therapies, the sequence of DSMs has more narrowly defined the illnesses which therapists treat, adding more specificity.  The DSM gives a numerical identifier for each diagnosis, along with decimal points after the numbers to indicate variations and severity.  Health insurance companies rely on the DSM to determine coverage.  If you don't have a number, you don't get reimbursed.  But they have become concerned about the multiplication of diagnoses, raising the number of claims.  Health insurance companies want to limit the number of diagnoses and limit the number of people diagnosed.

Weighing the Risks and Benefits - Will My Life Be Better?

"You have to weigh the risks and benefits."  That is what the doctor says.  It's your body, your decision, your responsibility.

But how do you weigh them?  There is that list of side effects.  They sound pretty scary, but the doctor assures you they are usually manageable.  Then there is the potential benefit of feeling better.  Well, that would be the gold ring, now wouldn't it?  Being able to get back to your family, your job, your life?

It's not a hard sell.  Reach out your hand and the pharmaceutical company will place in it that most precious of all commodities, hope.

Perverse little smarty pants that I am, after my hopes had been dashed six times, I started to read.  For four years I read journal articles about clinical studies.  The basic format begins with a measurement of depressive symptoms, usually the Hamilton Rating Scale for Depression, HAMD, depressed mood, suicidal ideation, sleeplessness, loss of appetite, etc.  You get points for severity.  Unlike your junior high math exam, the higher the score, the worse off you are.  In fact, if you ace this test, they will administer electric shocks to your brain (yes, I know, you will be unconscious at the time and won't feel a thing) until you forget how bad you feel and get a lower score.

So there are two groups, as alike as possible, Group A averages a HAMD score of 21.6, Group B's average is 22.1.  That's the mid range for moderately depressed, and the typical test subject score.  They don't include you in medical trials if you keep getting a high score, because now it's the medication that is being tested, and they want an audience that is easier to please.  Group A gets the medication being tried, Group B gets the placebo.  After 8 weeks, Group A's HAMD score is 8.2, Group B's score is 10.9, both in the mildly depressed range, but the difference is "statistically significant."  [That would depend on how big the sample is, and I am not doing the math.]  More people in Group A than Group B reached remission, a HAMD score of 6 or less.  A certain number dropped out because of side effects, so they don't count.  And there we have it.  The medication improves depressive symptoms by a statistically significant amount and is well tolerated, and you should get yours today.

But you know what?  That study with all its statistics did not answer your question.  Will you feel better?  Will you get your life back?  It told you what the odds are that your depressive symptoms would be reduced.  But that is not the same thing.  Not at all.

For example,the truck driver who is sad, not sleeping well, has no appetite, worries a lot and feels guilty is given Zoloft by his family practitioner.  Now he's eating better and is learning to put past sins behind him.  But he is too dizzy to drive, gets in fights with his friends and can no longer satisfy his wife, or even himself in bed.  So he decides to quit his meds.  The doctor is focused on his HAMD score and is very concerned, convinces him to try another med, then another.  But each time he gets the same side effects, and meanwhile has lost his job.

The truck driver has weighed the risks and benefits, asking is my life better? No, it isn't.  Let's hope his doctor knows that Cognitive Behavioral Therapy is often as effective as antidepressants for mild and moderately depressed people.  Ditto aerobic exercise, which could help his lose those extra pounds, improve how he feels about himself, and change the nature of what happens when they turn out the lights.

It turns out there are lots of psychological tests.  Many try to do what the HAMD does, and their inventors think that their tests do it better -- measure depressive symptoms.  But there is also a test that asks the real question: Are the lives of the people who take this medication better?  The Sheehan Disability Scale is a three question test, answered by the patient.  On a scale of 1-10, how much have the symptoms disrupted your work/school, your social life, your family/home responsibilities this past week?  It's simple.  It's easy.  It's what the people who are taking the meds want to know, will my life be better.  The people doing the research are focused on symptoms, not on the patient's life.  So that is how I read journal articles for four years and had never heard of the Sheehan Disability Scale (SDS).

For some reason, the clinical trials for Abilify decided to ask the patient's question, using the SDS.  Actually, they used seven different tests.  When the journal articles came out, they reported only one, the Montgomery-Asberg Depression Rating Scale (MADRS), a substitute for HAMD.  My September 4 post, OMG!! That's What They Said! Significant, reported its not particularly impressive, but FDA passable,  "statistically significant reduction in depressive symptoms."  The other test results disappeared.

But somebody noticed, and called them on it.  That is when I learned that the SDS even existed.  Why would they go to all the trouble of doing seven different tests, and then publish the results of only one?  Turns out that while Abilify.com says that "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," as far as the people who actually swallowed the stuff were concerned, it was a wash.  When you weigh symptoms and side effects, they reported that there was no improvement in their work/school life, a little improvement in family life.  But overall, it was a wash.

What was the author's response?  "Robert Berman from Bristol-Myers Squibb wrote... "this may be due to the lower sensitivity" of the measure."  I got that from "Abilify, Depression and the Memory Hole" at clinpsyc.blogspot.com.  Robert Berman, chief author of the research report, is not only an employee of Bristol-Myers Squibb, his compensation also includes stock options -- a little side note on how medical research is conducted in a for-profit health care system.

Okay, so the Sheehan Disability Scale is not sensitive enough to pick up what were pretty small decreases in depressive symptoms anyway.  That isn't its purpose.  What it will do is weigh your risks and benefits. Will Abilify improve my life, at work, at home, at play?  Nope.  Not if you are taking it for depression.  It won't.

What Prozac Monologues wants to know is what the Sheehan Disability Scale would tell me about Lamictal, the medication I have just added to my antidepressant instead of Abilify.  But as far as I know, nobody asked.

photo by Hans Anderson, This file is licensed under the Creative Commons Attribution ShareAlike 3.0

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 Chemistry 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.