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Recently, many psychologists, psychiatrists, the general public, and the media have been becoming more aware of bias in pharmaceutical research. The most recent work found that researchers design the study in order to favor the medication that is sponsored by the funding source. In this post, I will talk about some of the problems with pharmaceutical study research design.
The Placebo Washout Phase
Nearly all studies of pharmaceuticals, at least psychotropics, include an initial phase in which people who respond (read benefit) from a sugar pill are excluded from the study. So, if in the initial phase, they get better on placebo, they are excluded from the study. Purportedly, this is to remove an unimportant variable. But what this does is amplify the effects of the medication in the actual study. So, the drugs end up looking like they have a greater effect than they actually have. You end up with a group of folks who purportedly do not respond well to placebo taking an active drug versus a sugar pill. If you are going to run this type of study, the results need to state, “For people who are poor responders to placebo, the drug proved to be moderately efficacious.” That would be a more honest way to present the results, but I have never seen this occur. The exclusion of ‘placebo responders’ amplifies the effect of the ‘drug.’
Use of Percentages in Results
I have seen a number of popular drugs tested against placebo and the only statistics you find in the article to be “percent who achieved remission.” You read the whole article and the only thing presented is percentages and statistics to tell you if the percentages who fall into certain groups differ. This is also done so that the drug looks better than placebo. As an example, please see my previous analysis of on a study of antidepressants (Prozac) in children.
The Double Blind is not Blind
The double-blind research design is considered to be the ‘gold standard’ in pharmaceutical research. It is purported to be the most objective and best way of determining whether or not a drug has efficacy. The double-blind experiment is accurately described on Wikipedia:
Double-blind describes an especially stringent way of conducting an experiment, usually on human subjects, in an attempt to eliminate subjective bias on the part of both experimental subjects and the experimenters. In most cases, double-blind experiments are held to achieve a higher standard of scientific rigour.
So, the assumption is that the researchers do not know which group the study participants have been assigned, and the participants do not know which group they have been assigned to. Ah….but there’s a problem here. Previous research with antidepressant medication, reveals that both patients and doctors are pretty good at figuring out which group they are in, most likely because of side effects.
Some Solutions to the Problem
If you are reading pharmaceutical research that does not include a check to see if the blinding actually worked (in other words ask the researchers or physicians what group they think the participant is in and ask the participant what group they think they are in), uses a placebo washout phase, and only uses percentages or stats to tell if the percentages differ, be very skeptical of this research. Irving Kirsch has proposed a model for research that includes an ‘active placebo,’ in other words a drug that produces side effects, but in theory does not act in the same way as the drug. This should help to actually insure the ‘blind’ of the study. Finally, when research is funded by a pharmaceutical company, you need to be very skeptical of the results. If researchers are going to receive pharmaceutical industry funding, they need to be blind to the ‘who’ is funding them.
After I ended my last post, I got to thinking that maybe Irving Kirsch already had something to say on the matter of the effectiveness of antidepressants for children. Turns out, he did.
Basically, on the very limited number of studies that were available, he found the same thing for SSRIs that he found with adults–75% of the effects of SSRIs was duplicated by placebo. For tricyclic antidepressants, it was 98%. He concluded that SSRIs did not offer a clinically significant difference over placebo, and TCAs were completely ineffective.
So, my advice would be to first consider psychotherapy, unless the depression is very severe to the extent that the child or adolescent has a great deal of difficulty in functioning. Certainly, you want to have a thorough physical examination with a physician as the first step to rule out any physical causes.
Now, there are many (probably most) psychotherapists will recommend antidepressants anyway, because that is the way they’ve been trained. But there are those out there who will support your efforts to overcome your mild to moderate depression without medication. I would want to try that first with children for two reasons. The first is that we do not know what the long-term effects of these medications are on the brain. The second is a philosophical communication (or unconscious communication) that occurs when you take medication versus participate in psychotherapy. I think the communication with medication can often be that there’s something wrong with your brain. You needn’t bother changing anything in your life, just take this pill. At least with psychotherapy there can be the communication that something is wrong in your life, in your relationships, in the way you think, in internal conflicts that need to be resolved, or in your activity level that needs to change. It’s a matter of teaching people to be in control of their lives versus teaching them they are controlled by their biology.
That’s what the latest study published in the American Journal of Psychiatry says. In a nutshell, they initially selected their subjects based on whether they were depressed and were excluded based on a number of factors (one of which was previous failure to respond to prozac or adverse reactions to prozac). All of the participants were initially tried on prozac, with dosage increases in waranted. Those who didn’t respond to prozac were excluded from the continuation phase. Then they were randomly assigned to continue on prozac or placebo. So, the placebo group is abruptly taken off of prozac and put on sugar pill while prozac group experiences no such disruption. The authors thought this was okay because of prozac’s “long half-life.”
The study found that 42% of the prozac group relapsed within 6 months, whereas 69% of the placebo group relapsed. With an even stricter measure of relapse, only 22% of prozac group relapsed, whereas 48% of the placebo group relapsed.
This makes prozac sound pretty good for kids, does it not?? It does….
But there’s a catch. I’ll just focus on the “stricter” measure of relapse for now. This was based on scores on a scale that measures sympoms of depression the CDRS-R. Scores >= 40 over two sessions with a psychiatrist (separated by 2 weeks) were considered to be relapses, whereas scores under 40 were not considered to be relapses. How do we know whether 69% of the prozac group didn’t have scores of 39 (not relapsed), whereas 69% of the placebo group had scores of 41 (relapsed)?? We don’t know, because we don’t know any scores. We don’t know if the differences are truly clinically significant, because we don’t know what the differences in the actual scores were.
Also, the fact that the study was set up to only include people who respond to prozac, we know nothing about how this would work if applied to the general population of children who are depressed. In other words, the deck was stacked in prozac’s favor. The authors, in my opinion, just seemed to gloss over the possibility that the increased “relapse” in the placebo group could have been caused by the abrupt discontinuation of prozac.
I suppose we’ll have to wait another 10 years for Irving Kirsch to publish an analysis on whether antidepressants provide any clinically significant benefit over placebo. I, for one, am not convinced by this poorly designed and written study.
Well not actually duds. Just good placebos. I’ve posted on this before and the data keeps coming in (See this article). The previous studies were extended to include the newer generation of antidepressant medication (fluoxetine, venlafaxine, nefazodone, and paroxetine).
All studies are biased and have an agenda. The Last Psychiatrist thinks that reporting on this story in the press is a move to promote antipsychotics for depression. I’d say that’ll probably happen.
The fact is, there is a large proportion of people who are depressed, and don’t want to think about psychotherapy or go through the process. They would prefer to take a pill. So, don’t worry, the pills will still be there. Only now, they’ve got worse side effects….
I’m a psychologist, and so my bias is towards psychotherapy. Very few of my patients, want, or take, medications. That said, I believe a signfiicant portion of people who take antidepressant medication would prefer psychotherapy if they were given the option. The majority of antidepressants that are prescribed in the nation are prescribed by the family doctor. Even though I work in “the sticks,” I am not hurting for business. However, there are a lot of psychologists in the field who struggle to build a practice. This is good news if it leads to more people recieving psychotherapy instead of medication; however, I don’t think this is very likely to occur. What’s more likely is a new set of biased data promoting the next wonder drug…. And again, this is OLD news. Studies like this have been around for 10 years, and now with the antidepressant patents running out… Suddenly, everybody takes notice….
Back in graduate school, I began to speculate about the nature of the placebo effect and psychotropic medication. I did many literature searches and read as many articles as I could find on the subject. What I discovered was the placebo effect is a powerful demonstration of the interaction between mind and body, and that the effects of many medications can be largely explained by this effect despite attempts at experimental rigor with double-blind experiments.
The review article by Kirsch and Sapirstein (1998) comparing the efficacy of antidepressant medication to placebo. One of their findings was that 75% of the effects of antidepressant medications could be explained by the placebo effect. Indeed, it was further suggested that the remaining 25% of the effect could be due to an active placebo effect. Meaning that because of side effects, the participants figured out they were in the active drug group, which enhanced their beliefs that they would benefit. Because of my research on cognitive dissonance, I speculated an additional possibility for why side effects enhance the placebo effect. When people suffer as a result of something that they believe will be helpful, this sets up an inconsistency of beliefs that must be resolved (”I’m taking this antidepressant medication, but I have trouble with sexual functioning now….But you know it’s worth it, because this is really helping me!”) So, the medication comes to be more valued because of the side effects, not in spite of them.
My dissertation was on cognitive dissonance (how people react and change their beliefs unconsciously when they are inconsistent). Cognitive dissonance theory might predict that people might believe that they are being helped more by a medication that actually has a slightly negative effect as opposed to a true placebo (such as a sugar pill). Additionally, dissonance would be increased by paying for the medication. Therefore, I would expect that people who pay for medication out of their pockets might have a somewhat better effect with medication. Generally, enhanced placebo effects from medications would need to a nuisance and not extremely negative. In other words, it’s difficult to develop a positive attitude about a medication with a serious negative effect. However, the more serious the condition, the greater the negative side effects could be, and the person could still come to the conclusion “I have these horrible side effects, but you know, it’s worth it because I feel better.”
Beliefs are powerful in all emotional disorders. If you truly believe something is beneficial, it usually will be. This also applies to some extent to a lot of physical disorders. Kirsh and others recommend that experimental procedures for medication be revised to include an active placebo group (a group that takes medication that causes some similar side effects), so that the true effectiveness of medication can be determined. I support this idea wholeheartedly.