As head of Lilly’s early-stage psychiatric drug development in the late ’90s, Potter saw that … the company’s next-generation antidepressants were faring badly, too, doing no better than placebo in seven out of 10 trials. … Potter discovered, however, that geographic location alone could determine whether a drug bested placebo or crossed the futility boundary. By the late ’90s, for example, the classic antianxiety drug diazepam (also known as Valium) was still beating placebo in France and Belgium. But when the drug was tested in the US, it was likely to fail. Conversely, Prozac performed better in America than it did in western Europe and South Africa. It was an unsettling prospect: FDA approval could hinge on where the company chose to conduct a trial. …
The trouble with your argument is that placebos are known to be effective. There is actual medical value to prescribing a placebo ... particularly if the person is non-responsive to existing antibiotics.
Did you know that:The proportion of Americans using antidepressants in a given year nearly doubled from 5.8% in 1996 to 10.1% in 2005. APalling, big pharma wom.Maybe it is due to the placebo efect, cause they are afraid that is is shown to the public that other things work.Some think it is the process of administering it. It is thought that the touching, the caring, the attention, and other interpersonal communication that is part of the controlled study process (or the therapeutic setting), along with the hopefulness and encouragement provided by the experimenter/healer, affect the mood, expectations, and beliefs of the subject, which in turn triggers physical changes such as release of endorphins, catecholamines, cortisol, or adrenaline. The process reduces stress by providing hope or reducing uncertainty about what treatment to take or what the outcome will be. The reduction in stress prevents or slows down further harmful physical changes from occurring. The healing situation provokes a conditioned response. The patient's been healed before by the doctor (or thinks she's been healed before by the doctor) and expects to be healed again.
Doctor's cannot prescribe placebos as it is considered unethical to prescribe an inactive compound. As you say, we often will give innocuous medications or change to another drug in the same class if the first one doesn't work which is getting close to placebo.
And anyone who thinks benzos only work as well as placebo has never met a patient with anxiety disorder. Short-term use is very effective, long-term is not.
Alan
There was a great article on the Placebo Effect at Skeptic Magazine here which answers your questions.
Pain and the resulting suffering are actually distinct neurological phenomena, although they are typically strongly coupled in neurologically intact people. Pain is a pure informational damage-report sent to the brain. This signal is processed by the insular cortex, a brain structure that handles many functions related to homeostasis and emotion. People with pain asymbolia perceive and recognize pain but do not suffer from it.
The placebo responsiveness of pain makes me wonder what the function of pain is. Analogising the human body to a warship I've always thought of pain as like the warning lights on the damage control panel. When Alpha Turret is on fire the Alpha-Turret-Fire light is on (and boy does that hurt). When the damage control crew extinguish the fire, the light goes out and the pain stops.
But maybe pain is higher up the chain of command. Damage control reports are fused with an appreciation of the tactical situation to produce pain that modulates behaviour in the obvious way without being impossible to over-ride if the strategic situation demands it. So after a hit on Alpha Turret the Alpha-Turret-Fire light comes on. Another hit starts a fire close to the magazine. Then the Alpha-Turret-Fire light goes out; Alpha Turret is still on fire but the tactical situation demands that damage control crews go to fight the fire threatening the magazine. Perhaps the captain will over-rule this, unless the forward turret can be brought back into action the approaching enemy torpedo boat will sink the ship anyway.
Scuttling the nautical metaphor and returning to the body, pain has an obvious role of modulating behaviour so as to rest an injury and then to gradually bring the affected limb back into use as it heals. Suppose that pain is integrating both the degree of damage and an instinctive estimate of how much rest is a good trade-off between healing and being out of action. Perhaps the instinctive estimate is sophisticated enough to pick up on the idea that the magic medical pill will take care of the healing, so rest is no longer required and activity need not be discouraged. Result: pain relief.
Perhaps placebo effects are sensitive the fine distinction of whether the patient thinks of a pill as paliative or curative. Since it is probably the patients subconscious beliefs that matter to the bodies pain system, this is probably hard to research.
I agree with Ben A's points. Anxiety, depression, and chronic pain are notable for their degree of placebo responsiveness, as I recall. And that probably goes a long way towards explaining why a diazepam trial could fail to beat placebo.
Variable sensitivity is probably an issue here too, and leads to a lower trial dose. If you hit a set of anxious people with an "elephant dose" of diazepam, they would probably all respond very strongly indeed - but such a dose wouldn't be appropriate for everyone (would put some to sleep), and wouldn't be used in the trial.
Perhaps chronic effectiveness is also a problem. The acute efficacy is certainly high but if someone did a trial of chronic use (over a month) it might be hazier due to tolerance.
> Since depression is a “disease” with no physical cause or effect, treatment by placebos, which have no physical effect, would appear to be entirely appropriate.
Robert Speirs, it's exhilarating that you have plumbed the depths of the brain, and penciled in the neuron-level details of how each one of the several different human mind-states is produced. How singular that you were able to get so far ahead of the scientific community at large. Just ten years ago, diseases like narcolepsy were having a physical basis in the brain discovered all of a sudden, after generations of mystery (hypocretin) - now we will experience no more such shocks. I eagerly await the full report from your lab, and for the nonce can only bow very low indeed before one of the greatest men of all time.
Suggesting that a brain state has no physical cause or effect is patently absurd. You can't "cure" depression but you can treat it as an undesirable brain condition that can be changed into a different condition by the administration of various drugs. It's no different than, say, someone who doesn't want to be sober who consumes alcohol in order to modify his state of mind, just like I will be doing later tonight.
Shouldn't they already be made to look the same? This seems less about the ineffectiveness of pharmaceutical drugs than the effectiveness of placebos. If a blue placebo doesn't calm Italian men but a blue drug does, while a red placebo performs the same as a red drug, the trial is saying that blue drugs work... but no better than red placebos. Then the question is whether red drugs perform better than blue ones, etc. If these variables aren't already controlled then the trials are worthless.
do you think drug companies will use their better understanding of placebo effects to help us all better distinguish effective from useless drugs, or do you think they will instead use it to game the FDA approval process, to make more of their drugs look better than placebos?
1. Placebo effects must be studied. If something has a real effect, then it needs to be analyzed.2. Misuse is in the eye of the beholder. If a drug is made to look better than a placebo, then how is it not?3. An example of why placebo effects need to be studied: if we have more "lifestyle" drugs, then we need to determine how much of the improvement is chemical and how much is lifestyle improvement related to the constant reminder of taking the pill. People seem to eat less saturated fat if they're on Lipitor and less salt if they're on an ACE inhibitor. Pull those apart to see which effect is chemical.
I agree with the others that, for ethical (and probably practical!) reasons, doctors shouldn't exploit the placebo effect by prescribing known placebos.
However, it seems that the medical community's near-top priority right now should be to study why the placebo effect exists at all, so that it can be used in a more controlled, predictable, and ethical way. I mean, seriously, you've got patients who can be tricked into reacting to saline solution as if it were morphine, and you don't want to learn what neurological process is going on so it can be tapped some other way?
The question should be, "how can there be a placebo effect at all?" not "how can we better conduct placebo trials?" (although of course the latter is important too)
jobs in life SciencesYour Information is so Informative.
The trouble with your argument is that placebos are known to be effective. There is actual medical value to prescribing a placebo ... particularly if the person is non-responsive to existing antibiotics.
Did you know that:The proportion of Americans using antidepressants in a given year nearly doubled from 5.8% in 1996 to 10.1% in 2005. APalling, big pharma wom.Maybe it is due to the placebo efect, cause they are afraid that is is shown to the public that other things work.Some think it is the process of administering it. It is thought that the touching, the caring, the attention, and other interpersonal communication that is part of the controlled study process (or the therapeutic setting), along with the hopefulness and encouragement provided by the experimenter/healer, affect the mood, expectations, and beliefs of the subject, which in turn triggers physical changes such as release of endorphins, catecholamines, cortisol, or adrenaline. The process reduces stress by providing hope or reducing uncertainty about what treatment to take or what the outcome will be. The reduction in stress prevents or slows down further harmful physical changes from occurring. The healing situation provokes a conditioned response. The patient's been healed before by the doctor (or thinks she's been healed before by the doctor) and expects to be healed again.
bellisaurius
Doctor's cannot prescribe placebos as it is considered unethical to prescribe an inactive compound. As you say, we often will give innocuous medications or change to another drug in the same class if the first one doesn't work which is getting close to placebo.
And anyone who thinks benzos only work as well as placebo has never met a patient with anxiety disorder. Short-term use is very effective, long-term is not.
Alan
There was a great article on the Placebo Effect at Skeptic Magazine here which answers your questions.
http://www.skeptic.com/eske...
the system is too risk-averse; it takes way too long for important drugs to be approved
Perhaps so, but that is no reason for a drug to get approved if its sponsor is willing to defraud the FDA and denied it if its sponsor is unwilling.
Pain and the resulting suffering are actually distinct neurological phenomena, although they are typically strongly coupled in neurologically intact people. Pain is a pure informational damage-report sent to the brain. This signal is processed by the insular cortex, a brain structure that handles many functions related to homeostasis and emotion. People with pain asymbolia perceive and recognize pain but do not suffer from it.
The placebo responsiveness of pain makes me wonder what the function of pain is. Analogising the human body to a warship I've always thought of pain as like the warning lights on the damage control panel. When Alpha Turret is on fire the Alpha-Turret-Fire light is on (and boy does that hurt). When the damage control crew extinguish the fire, the light goes out and the pain stops.
But maybe pain is higher up the chain of command. Damage control reports are fused with an appreciation of the tactical situation to produce pain that modulates behaviour in the obvious way without being impossible to over-ride if the strategic situation demands it. So after a hit on Alpha Turret the Alpha-Turret-Fire light comes on. Another hit starts a fire close to the magazine. Then the Alpha-Turret-Fire light goes out; Alpha Turret is still on fire but the tactical situation demands that damage control crews go to fight the fire threatening the magazine. Perhaps the captain will over-rule this, unless the forward turret can be brought back into action the approaching enemy torpedo boat will sink the ship anyway.
Scuttling the nautical metaphor and returning to the body, pain has an obvious role of modulating behaviour so as to rest an injury and then to gradually bring the affected limb back into use as it heals. Suppose that pain is integrating both the degree of damage and an instinctive estimate of how much rest is a good trade-off between healing and being out of action. Perhaps the instinctive estimate is sophisticated enough to pick up on the idea that the magic medical pill will take care of the healing, so rest is no longer required and activity need not be discouraged. Result: pain relief.
Perhaps placebo effects are sensitive the fine distinction of whether the patient thinks of a pill as paliative or curative. Since it is probably the patients subconscious beliefs that matter to the bodies pain system, this is probably hard to research.
> Placebo creep can be a real problem
I agree with Ben A's points. Anxiety, depression, and chronic pain are notable for their degree of placebo responsiveness, as I recall. And that probably goes a long way towards explaining why a diazepam trial could fail to beat placebo.
Variable sensitivity is probably an issue here too, and leads to a lower trial dose. If you hit a set of anxious people with an "elephant dose" of diazepam, they would probably all respond very strongly indeed - but such a dose wouldn't be appropriate for everyone (would put some to sleep), and wouldn't be used in the trial.
Perhaps chronic effectiveness is also a problem. The acute efficacy is certainly high but if someone did a trial of chronic use (over a month) it might be hazier due to tolerance.
> Since depression is a “disease” with no physical cause or effect, treatment by placebos, which have no physical effect, would appear to be entirely appropriate.
Robert Speirs, it's exhilarating that you have plumbed the depths of the brain, and penciled in the neuron-level details of how each one of the several different human mind-states is produced. How singular that you were able to get so far ahead of the scientific community at large. Just ten years ago, diseases like narcolepsy were having a physical basis in the brain discovered all of a sudden, after generations of mystery (hypocretin) - now we will experience no more such shocks. I eagerly await the full report from your lab, and for the nonce can only bow very low indeed before one of the greatest men of all time.
Suggesting that a brain state has no physical cause or effect is patently absurd. You can't "cure" depression but you can treat it as an undesirable brain condition that can be changed into a different condition by the administration of various drugs. It's no different than, say, someone who doesn't want to be sober who consumes alcohol in order to modify his state of mind, just like I will be doing later tonight.
Shouldn't they already be made to look the same? This seems less about the ineffectiveness of pharmaceutical drugs than the effectiveness of placebos. If a blue placebo doesn't calm Italian men but a blue drug does, while a red placebo performs the same as a red drug, the trial is saying that blue drugs work... but no better than red placebos. Then the question is whether red drugs perform better than blue ones, etc. If these variables aren't already controlled then the trials are worthless.
do you think drug companies will use their better understanding of placebo effects to help us all better distinguish effective from useless drugs, or do you think they will instead use it to game the FDA approval process, to make more of their drugs look better than placebos?
Both, more of the latter.
Actually if you read the article they do try to use the placebo effect, prescribing drugs they know are ineffective, or in ineffective doses.
1. Placebo effects must be studied. If something has a real effect, then it needs to be analyzed.2. Misuse is in the eye of the beholder. If a drug is made to look better than a placebo, then how is it not?3. An example of why placebo effects need to be studied: if we have more "lifestyle" drugs, then we need to determine how much of the improvement is chemical and how much is lifestyle improvement related to the constant reminder of taking the pill. People seem to eat less saturated fat if they're on Lipitor and less salt if they're on an ACE inhibitor. Pull those apart to see which effect is chemical.
It isn't about pharma's motivations, but Mind Hacks had an interesting response:http://www.mindhacks.com/bl...
I agree with the others that, for ethical (and probably practical!) reasons, doctors shouldn't exploit the placebo effect by prescribing known placebos.
However, it seems that the medical community's near-top priority right now should be to study why the placebo effect exists at all, so that it can be used in a more controlled, predictable, and ethical way. I mean, seriously, you've got patients who can be tricked into reacting to saline solution as if it were morphine, and you don't want to learn what neurological process is going on so it can be tapped some other way?
The question should be, "how can there be a placebo effect at all?" not "how can we better conduct placebo trials?" (although of course the latter is important too)