They suggest that maybe it's the patients fault:
Participation that is induced by cash payments may lead subjects to exaggerate their symptoms [i.e. in order to get included into the trial]... Another contributing factor to high placebo response rates may be the extent to which the volunteers in antidepressant trials are really generalizable to patients in clinical practice.
Since the initial antidepressant trials in the 1960s, participants have gone from being patients who were recruited primarily from inpatient psychiatric populations to outpatient volunteers who are often recruited by advertisements. At times, these symptomatic volunteers have participated in other trials. When we contact potential participants to schedule screening, they often ask to be reminded which trial we are screening for or mistake our research trial for a different protocol in which they recently participated.They then recount the tale of two "professional subjects" who claimed to be depressed and enrolled in two antidepressant trials simultaneously, without telling the researchers; it only came to light when someone involved in both studies spotted the duplicate names.
I've been the victim of such nonsense myself, as have many of colleagues - it's a perennial watercooler topic. A few years ago I was running a study recruiting people who'd recovered from psychiatric illness. The main source of volunteers was online adverts.
That study was a learning experience. What I learned is that House was right. We recruited about 20 people. No fewer than 3 turned out to have enrolled in other studies and lied about it. After I realized this I Googled the offender's names and two of them turned up in the court pages of the local newspaper pleading guilty to various petty crimes.
Another volunteer was left handed and, upon realizing that I was only recruiting right-handed people, discretely switched his pen to his right hand and then took 5 minutes trying to fill out a form with his off hand. He didn't make it in, but if I hadn't been paying attention he would have.
So yes, it is a problem. However, it would have to be taking place on a massive scale for it to be having a significant effect on antidepressant trial results and this really seems pretty unlikely.
In my view, the authors miss out on the real problem with recruiting depressed people through adverts: depressed people don't tend to respond to adverts, because depressed people don't do anything. That's why they call it depression.
Getting recruited into a modern clinical trial is actually quite a challenge. There are many pieces of paper to fill in, calls to return, appointments to attend. Turn up late to the screening visit, or otherwise make life difficult for the study staff, and you'll be marked down as "unreliable" and they'll find someone who plays by the rules. Modern trials are very expensive. The last thing a study sponsor wants is a volunteer who will end up forgetting to take their pills on time.
Depression, unfortunately, makes you bad at doing things. You procrastinate, you forget, you put things off until too late, you have a change of heart and decide not to, you get cold feet, you can't be bothered... That goes for things as simple as cooking dinner in severe cases, let alone something as complicated as taking part in a trial.
So while you wouldn't go looking for aquaphobic people in a swimming pool, I'm not sure we should be looking for depressed people through adverts.
Brody B, Leon AC, and Kocsis JH (2011). Antidepressant clinical trials and subject recruitment: just who are symptomatic volunteers? The American journal of psychiatry, 168 (12), 1245-7 PMID: 22193668
21 comments:
Or are you a bad person by recruiting only right-handed people for your study, thereby discriminating against a 12-15% segment (largely superior, of course) of our society?
Right on. These symptomatic volunteers are pretend patients who are given the pretend diagnosis of major depression based on a pretend assessment (structured interview) using a pretend criterion (checklist of symptoms).
of whom some receive a pretend treatment (placebo)
Another thing I just thought of: in most trials it takes a good deal of time to go from application to screening to baseline visit to actually starting the drug or placebo.
I don't know what the average is but I can't believe it's less than 3 or 4 weeks. Maybe much more if the trial is understaffed / oversubscribed.
But depression is episodic. If you're depressed when you see the advert that's no guarantee you will still be depressed 4 weeks later. You might have recovered or at least be on the way to being better.
But of course you won't say that. Once you've committed to being in the trial and getting the payment you're not going to tell anyone that.
Time of year also counts.... Almost anyone has some form of SAD. That's how the body works.
I am afraid-being a bitter middle age modest clinician- that many clients will lie also to the GPs or the busy psychiatrists in a regular visit-
And you do not want to select the more honest people if you want to have a representative sample of the population who will receive the drugs.
I always was one not liking to prescribe much and before that not liking to ingest much drugs but as a student in medicine I had friends who did participate for big enough money in pre-clinical trial of drugs (toxicity, pharmacocinetics) and I could see some smoking or eating barbecue in summer when under pharmacocinetic studies...
Those who tell lies for money to enter a trial will tell lies to get free paid holidays, a useful paper for a divorce procedure or blackmailing a partner into staying with them, in order to get advantages on the work place.You name it.
Unless you work with aspies and i would love to work full time for aspies...
When I was doing a lot of pro bono in an informal way for an association of parents of gifted children or homeschooling parents I benefit -in some intyelectual ways- from a friendly ambiguous status. Refusing to prescribe Big Pharma drugs (but sending some people to other psychiatrists) I was astonished to discover how many people were seing several physicians at the same time (some homeopath physician with a high frequency),
plus many types of healers from the chinese herbals vendors and the oriental massages to some psychotherapic gyms and Big Pharma like supplement ,
plus following many diets (in positive and negative) and
many spirituals paths
plus automedication and not taking the prescribed drugs.
I knew it existed but I was astonished of the scale of it.
For the neuroskeptic comment:
so true but - How to avoid it unless you change completely the way to do clinical research and work in a real "recovery" manner with the clients and the many clinicians treating them:
I think the clients and the GPs are the hope of clinical research.
What nonsense. In treatmnt settings, when the patient doesn't get better, we blame the patient, not the medication. Why the patient is "treatment-resistant" or she is a "non-responder." The problem is with the patient, not the pill. And that's what Psychiatry is doing here to explain failed clinical trials: Blame the patient again!
What is the reason for not recruiting antidepressant trial populations from inpatients? This would seem to be a more appropriate patient group, especially given recent meta-data that antidepressants are more effective in severe depression.
Sciencetwat:
Because Big Pharma doesn't want the market for their pills to be limited to inpatients with severe depression. They want as many people in the community as possible popping pills. They make more money that way.
"depressed people don't tend to respond to adverts, because depressed people don't do anything. That's why they call it depression."
This is very very true. Been there. Didn't do that.
The only clinical type study I've ever been involved in (my living people research has all been with 'free ranging' subjects) involved lactation. Subjects were recruited via brochures carried by health professionals starting up relationships with pregnant women who intended to breastfeed. Those potential subjects were then screened, selected, sampled among, etc. etc. (For a total of a small but adequate number of individuals.)
Nobody faked being pregnant it turns out!
Seems to me, a good way to develop a sample for depressed individuals would be to recruit through practitioners (psychiatrists and psychologists working with psychiatrists). That would produce far superior results, I would think.
Isn't it about time we did a trial to assess the way participating in trials affects our behavior?
John,
It is why we should rethink completely the way we do trials.
of course in France the real emergency is the academic and experts on payroll from Big Pharma and chums like breast and testicules implants makers, respiratory machines etc...
sciencetwat,
Actually it remain to be seen that the most severe cases get to be hospitalized.
Like suicide to become e in-ward client is the result of many factors very often and even when it follow suicidal attempt...
The family or friends attitude and the physician in charge attitude etc...
You see everything even the blackmail of sibling or significant other to make you hospitalize a person-not to speak about the police in Parissince they have a special psychiatric unit outside of the right and law.
Anonymous: "What nonsense. In treatmnt settings, when the patient doesn't get better, we blame the patient, not the medication. Why the patient is "treatment-resistant" or she is a "non-responder." The problem is with the patient, not the pill. And that's what Psychiatry is doing here to explain failed clinical trials: Blame the patient again!"
It's a tricky one, certainly this kind of reasoning can end up being patient-blaming, but I don't see it that way, I see it as being about the failure to make a good diagnosis on the part of the doctors.
There's no such thing as a "bad patient", well not unless you are Hitler's doctor.
But there is such a thing as a badly diagnosed patient and they will seem to be bad in the sense that they don't behave how they "should" (according to their diagnosis).
....
of course in France the real emergency is the academic and experts on payroll from Big Pharma and chums like breast and testicules implants makers, respiratory machines etc...
Ivana,
Just today I posted on my blog some comments on a Review paper I read: Cancer as a Metabolic Disease. This paper argues convincingly that the genome model of cancer is hopelessly limited in its explanatory power and ultimately misleads with respect to the etiology and treatment of cancer.
I have noted in reading of years gone by that there are a number of compounds that repeatedly demonstrate promise in treating cancers but are routinely ignored for follow up trials. These include: ginseng species, cannabinoids, DCA, and zeolite. All natural compounds, can't make a buck of ém.
The current emphasis on "receptor interception" has value but will never be sufficient. There are a wide range of other treatment modalities available that need to be explored. We will need Big Pharma and their drugs, I don't have a problem with that but I have a very big problem with the way the lure of money is driving research in some areas while seriously neglecting it in others.
John,
I am not competent into cancer research at all but even in psychiatry what you write is relevant.
And to be fair, the cancer cure researchers are more open than the psychiatrists looking into chinese herbal remedies for example.
Big ernough chinatown in Paris (actually two )and many people enthousiastic about some herbs when you are afraid of tiny mushrooms pulluting it and kidney destroying in clients etc...
More should be studied of course.
some research is just not done in certain directions
greg,
More non psychiatrists than psychiatrists are prescribing antidepressants, GPs mostly and geriatricians.
Plus, my guess would be that the GPs knowing the clients before the depression episode might well do better than psychiatrists and psychologists in recruting for trials of antidepressants-
Be it only because the clients might consult and come back to their GPs offices 2 weeks later with less of an effort than to a psychaitrist - one practical criteria is depressed moods for more than two weeks duration.
. . . or bad nosology?
It really strikes me as the height of arrogance to blame the patients for behaving incongruently with the diagnosis of MDD. Are we sure there isn't a problem with the Dx? What's MDD? Do we know? Is it really one disease? Is it a disease at all? The biopsychiatry camp says yes. They say the diseased organ is the brain. But what do all MDD brains have that all non-MDD brains don't? If it's relative to the individual, do we really have evidence that there's been a CHANGE in the brain of treatment-naive patients? And if so, are we sure that the brain change caused MDD rather than the other way around? Or is there some third or tenth factor causing both of these things? My understanding is that these questions aren't settled. Until they are, biopsychiatry needs to cool its jets, get a bit more humble, and stop blaming patients for not fitting what is, after all, only a theory -- and not a very well supported one at that.
I am currently participating as a sub-investigator in a clinical trial for a new antidepressant. It is extremely difficult to find appropriate patients for the study because the inclusion and exclusion criteria are very strict. At least 90% of patients do not qualify. Almost all patients referred from colleagues do not qualify because of comorbidity or chronicity. Inpatients are almost always excluded from these trials because they are almost always too suicidal or unable to consent.
I think that a minority of patients are actually these professional study participants. However, what winds up happening is that researchers and patients magnify baseline symptoms at the beginning of the trial so that a patient will meet the baseline severity criteria. It is not hard to do this with the HAMD, which is a USELESS PIECE OF JUNK (I could rant about it for days...). Inflated scores at the beginning of the trial will quickly deflate once the trial begins contributing to the placebo response. The important factor here is that a major portion of the placebo response is an artifact of score inflation. That means that the effect of placebo is magnified due to the trial design and much lower in real life.
Modern clinical trials have started incorporating "centralized raters" who review audio recordings of your sessions and independently decide whether a patient meets entry criteria for the study.
Here some data to support the idea of baseline score inflation:
Kobak, K.A., et al. (2010) Site Versus Centralized Raters in a Clinical Depression Trial: Impact on Patient Selection and Placebo Response. Journal of Clinical Psychopharmacology 30: 193-197
Thanks for the comment. Yeah initial score inflation is certainly a problem. I've used the HAMD myself a bit and it's easy to fudge. I remember one guy who had been waking up early, because of noise from a nearby construction site that had just started.
I gave him 0 but if I'd wanted to, I could have given him 2 for "late insomnia" and it would have been strictly true. & then you've got "physical" complaints, aches and pains etc, do you score them or not? They could well be psychosomatic manifestations of depression (whenever I get depressed I get a headache and IBS-type symptoms) But they could just be physical. There's no way of knowing, so, it's the rater's call...
Would be fun to do a study actually, take the same people, get some psychiatrists to do the HAMD on them after priming them to "want" high or low scores, see what happens.
The factors that contribute to score inflation are quite complex.
From a patient perspective, enrolling in a clinical trial may mean that you get better quality healthcare. Many people who enroll in trials are dissatisfied with "15-minute med check psychiatry" and a clinical trial is often seen as an opportunity to have a better assessment and close monitoring. Obviously, financial benefits of free meds and healthcare are important in some countries. However, where I work, we have universal healthcare and the main problem patients face is access to good quality service.
From a clinical researcher's perspective, there are both financial reasons and benevolent reasons to inflate scores. Pharma companies pay investigators using competitive enrollment; this means that your unit gets payed per patient you enroll and you are "racing" with other sites. Once the desired number of patients are enrolled into the study, they stop funding. The other aspect is that when you do see a patient who is suffering and is very invested in participating in a study, it feels horrible to turn them away because they are a few points below the cut-off on a rating scale, which often may not correspond to your own impression of their level of suffering. (If you look at the HAMD-17, it is highly dependent on somatic and anxiety symptoms and some patients who are quite depressed can get low scores). Imagine being depressed and being turned away from a study and told that you are "not depressed enough". Someone with depression will then often think "I'm more miserable that I've ever been in my life and now you're telling me that I'm not even good enough to be in your study!" I think that clinicians will inflate scores and relax entry criteria to avoid that situation.
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