Biotie Therapies 22 September 2014 The wizard of tOz Biotie's share price has underperformed the biotechnology sector over the last 12 months, we believe as a result of concerns over UCB returning rights to its key pipeline drug, tozadenant for Parkinson's disease. However, the return of Market capitalisation
Is it prozac? or placebo?Is it Prozac? Or Placebo?
New research suggests that the miracles promised by antidepressants may be largely due to the
placebo effect. Too bad there's no money to be made in sugar pills.
Janis Schonfeld recalls the events that started her on her recovery from 30 years of depressionwith snapshot clarity: the newspaper ad she saw in 1997 seeking subjects for an antidepressantstudy; the chair she was sitting in when she called UCLA's Neuropsychiatric Institute; the windowshe was looking out of when she first spoke with Michelle Abrams, the research nurse whoshepherded her through the trial. She remembers being both nervous and hopeful when shearrived at the institute, and a little uncomfortable when a technician put gel on her head, attacheda nylon cap shot through with electrodes, and recorded her brain activity for 45 minutes. Butmost of all she remembers getting the bottle of her new pills in a brown paper bag from thehospital pharmacy. "I was so excited," she told me. "I couldn't wait to get started on them." Within a couple of weeks, Schonfeld, then a 46-year-old interior designer, got quickly anddramatically better, able once again to care for herself and her husband and daughter, no longerso convinced of her own worthlessness that she'd consider killing herself. For the next twomonths, she came back weekly for more interviews and tests and EEGs. And by the end of thestudy, Schonfeld seemed to be yet another person who owed a nearly miraculous recovery tothe new generation of antidepressants -- in this case, venlafaxine, better known as Effexor.
But during her final visit to the institute, one of the doctors directing the research sat her down todeliver some disturbing news. "He told me I hadn't been taking a medicine at all. I'd been on aplacebo. I was totally shocked." So was nurse Abrams. Both women knew that half the testsubjects were getting placebos and that Schonfeld might be among them. But not only was shefeeling better -- she'd even experienced nausea, a side effect commonly associated with Effexor,so they had each assumed that she was in the drug group. Schonfeld was so certain of this thatat first she didn't believe the doctor. "I said to him, 'Are you sure? Check those records again.'"But there was no doubt. The brown bag contained nothing but sugar pills. Which didn't mean, hewas quick to add, that she was making anything up, but only that her improvement couldn'tpossibly be due to the pharmacological effects of the pills.
Schonfeld's experience is hardly unique, although you wouldn't know it from the ubiquitousadvertisements for antidepressants -- nor, if you were a doctor, would you know just howcommon it is from reading the medical journals. Psychiatrists and other mental-healthprofessionals (I am a practicing therapist) know that any given antidepressant has only about a50 percent chance of working with any given person. But what most people -- patients andclinicians alike -- don't know is that in more than half of the 47 trials used by the Food and DrugAdministration to approve the six leading antidepressants on the market, the drugs failed tooutperform sugar pills, and in the trials that were successful, the advantage of drugs overplacebo was slight. As it would hardly help drug sales, pharmaceutical companies don't publishunsuccessful trials, so University of Connecticut psychology professor Irving Kirsch and his co-authors used the Freedom of Information Act to extract the data from the FDA. What they found has led them, and other researchers who've investigated antidepressants' relatively poorshowing against placebos, to conclude that millions of people may be spending billions of dollarson medicines that owe their popularity as much to clever marketing as to chemistry, and sufferingserious side effects -- not to mention becoming dependent on drugs for healing they might beable to do without them -- in the bargain.
But many doctors remain convinced that antidepressants do work, that the flaw lies not in thecapsules themselves but in the studies used to evaluate them. Clinical trials can consume half adrug's patent life. And so pressure to bring the medicine to market leads researchers to adoptstrategies -- such as recruiting people whose depression is too mild to yield powerful results --better suited to clearing regulatory hurdles than generating useful scientific knowledge. That, andnot the power of suggestion, is why antidepressants barely outperform placebos, these scientistssay.
While some of this debate breaks down along familiar lines -- psychologists resisting thetendency to reduce all mental suffering to biology versus psychiatrists more comfortable withmatter than spirit -- no one disputes that the statistics about antidepressant efficacy are dismal,and that they do little to clarify the question of whether people who get better on antidepressantsdo so because they are taking Prozac or Zoloft or because they are taking a pill -- any pill.
BEFORE SCIENCE TOOK OVER the healing arts and focused physicians' attention onbiological causes of disease, mystics and alchemists and flimflam artists alike offered potionsand powders to the ailing. Some of these remedies were bizarre, like usnea -- the moss from theskull of a hanged man, used to treat nervous illness -- and others merely fanciful, like powderedunicorn horn. Some were truly dangerous, like calomel, a mercury-based laxative that may havehastened George Washington's death from the cold he famously caught while riding on a rainynight. Some -- notably cinchona bark, the source of quinine -- turned out to have actual healingpowers, but there were so few of these that in 1860 Oliver Wendell Holmes, the doctor whofathered a Supreme Court justice, wrote, "If the whole materia medica could be sunk to thebottom of the sea, it would be all the better for mankind and all the worse for the fishes." But Holmes was not entirely correct. Despite their lack of specific healing properties, manyancient medicines worked -- or at least people often got better after taking them, as they still do.
Most illnesses remit as part of their natural course, but the placebo effect occurs far toofrequently to be mere coincidence. No one really understands why, but doing something for anillness -- especially if that something involves a pill -- is usually better than doing nothing at all.
There's no money to be made in sugar pills, so drug companies, which fund much of the drug
research in the United States, have not looked very hard into this question. But placebos do
figure prominently in their studies -- as a stalking-horse for the potential new medications.
Because any drug may well be acting as a placebo, it is not a sufficient test simply to give a new
compound to sick people to see if they get better. To rule out the possibility that patients are
recovering because of faith or a good sales pitch, and to ensure that the drug works by virtue of
its biochemical properties, the FDA has, since the late 1970s, required that all drugs be tested
against placebos. Typically, between 35 and 45 percent of people given placebos improve. If a
candidate drug outperforms a placebo in two independent studies, and if it does so without
untoward side effects, the FDA will approve it for use.
The FDA does not consider, however, the relative advantage that new drugs show over placebo.
So long as the difference is statistically significant -- meaning that the results are not merely
random -- a drug can be advertised as "safe and effective" whether clinical trials proved it to be 5
percent or 50 percent or 500 percent more effective than an inert pill. In the case of the Prozacgeneration of antidepressants, marketing efforts have paid off wildly. Some 92 millionprescriptions were written for the top six antidepressants in 2002, a ubiquity that has, far morethan any research, helped to bolster the theory that depression is the result of a biochemicalimbalance that the drugs cure -- a theory that has not been proved, despite more than 40 yearsof trying.
But critics, psychologists and psychiatrists alike, have been suspicious of the drugs since theywere introduced, and it turns out they have some striking data on their side. "In the early '90s,many of our psychiatric colleagues felt that patients did not do as wonderfully as all these reportsof 'magic pills' would suggest," recalled psychologist Roger Greenberg, a professor at the StateUniver-sity of New York's Upstate Medical Uni-versity. "So we went back to the literature."Greenberg [no relation to the author] and his team analyzed all the data from Prozac's clinicaltrials that had been published. They determined that the new drug showed negligible advantageover earlier antidepressants and that two-thirds of the patients would do as well or better withplacebos.
Greenberg started with material hidden in the plain light of professional journals, but a bit of
detective work by Irving Kirsch and his research team has turned up even more disturbing
evidence about the low rates of antidepressant effectiveness. Kirsch is a soft-spoken and slight
man who has spent more than 30 years studying the placebo effect. He has a native suspicion of
biological explanations of depression and sees in the placebo effect the potential for self-healing
without resorting to expensive and possibly dangerous drugs. While many researchers
duplicated and refined Greenberg's initial findings, Kirsch knew that there was a body of results
that no one was looking at. Manufacturers don't have to publish all their data in journals, but they
do have to report every trial to the FDA. "This was all so controversial," he told me. "And the
defenders claimed that our data didn't tell the whole story. So we figured, why not use the
Freedom of Information Act to investigate?"
Kirsch requested the complete files on the six most widely prescribed antidepressants approvedbetween 1987 and 1999: Prozac, Zoloft, Paxil, Effexor, Serzone, and Celexa -- drugs thattogether had $8.3 billion in worldwide sales in 2002. Within a month, he had an even less drug-friendly story than the one told in the journals. In "The Emperor's New Drugs," published in theJuly 2002 issue of the American Psychological Association's Prevention & Treatment, Kirsch'steam presented their findings: Of the 47 trials conducted for the six drugs, only 20 of themshowed any measurable advantage of drugs over placebos, a much lower number than turns upin published research. This was not entirely unexpected -- "publication bias" has long beenknown to be a problem in assessing the effectiveness of drugs -- and Kirsch is quick to point outthat even these meager numbers "leave no doubt that there is a difference between drug andplacebo. But I was surprised at how small the difference was in clinical terms. The studies allused the same measure" -- the Hamilton Depression Rating Scale, the nearly universal wayclinicians assess a patient's level of depression -- "so it was easy to see how much clinicalimprovement there really was." And there really wasn't much at all: The average patient on drugsimproved by about 10 points on the 52-point Hamilton, while a placebo patient improved by alittle more than eight. "A two-point difference on the Hamilton -- it's just clinically meaningless.
Trivial," Kirsch says. "You can get that from having an improvement in sleep patterns, and if oneof the side effects of the drugs is to induce drowsiness, the whole difference could be rightthere." (Indeed, critics say the Hamilton is skewed toward physical symptoms of depression,those most likely to be affected by medication.) Kirsch received copies of memos indicating that regulators had, in at least one case, raised questions about clinical significance. In 1998, Paul Leber, then director of the FDA's Division of
Neuropharmacological Drug Products, wrote of Celexa, "There is clear evidence from more than
one adequate and well-controlled clinical investigation that [Celexa] exerts an antidepressant
effect. The size of that effect, and more importantly, the clinical value of that effect is not
something that can be validly measured, at least not in the kind of experiments conducted." A
deputy agreed: "It is difficult to judge the clinical significance of this difference," he wrote, but
added that this shouldn't be an impediment for bringing Celexa to market because "similar
findings for.other recently approved antidepressants have been considered sufficient."
Kirsch argues that by the FDA's own logic, it's not even clear if the drugs' small advantage is
truly pharmacological. In trials, every drug response is assumed to be partially a placebo
response, and the drug effect is only the additional benefit -- in the case of the antidepressant
studies, less than two points out of ten, or 20 percent of the overall improvement. This means, he
said, that "80 percent of the drug effect is the placebo effect." And even the remaining 20
percent could be due to placebo effects enhanced by the drugs' side effects, amplified by the
way the trials are conducted. "A person is brought into a clinical trial and told, 'You may be
getting placebo or drug. The real drug has the following side effects.' Put yourself in this position.
You're certainly curious about what you're getting. And you want to get better. You notice that
your mouth is getting dry, which is one of the side effects they told you about, and that leads you
to conclude that you've been assigned to the drug condition. Presumably, a placebo works by
affecting a person's expectancy about what is going to happen. If you know you've been
assigned to the drug con-dition, you may have a stronger placebo effect because you're now
more convinced that you're getting something that's going to help you." Greenberg's research
shows that both patients and raters in clinical trials often "break the blind" by guessing which
condition they have been assigned and that the most powerful drug effects are reported when
this occurs. The guesses don't even have to be accurate. Janis Schonfeld experienced side
effects on placebo, and this was part of what led her (and nurse Abrams, who was scoring the
Hamilton) to assume she was on drugs. According to Kirsch's theory, Schonfeld's strong
response (and Abrams' rating of her progress) may have come about because they thought --
due to symptoms caused by the power of suggestion -- that she was on the drug.
Kirsch thinks it is possible to test his theory, but only with a radical redesign of the method usedto validate drugs. Instead of two groups, a study would have four. Researchers would tell twogroups of patients they were getting placebo and the other two that they were being given thedrugs. But only half the patients would be told the truth. And the placebo would be anonpsychoactive substance designed to mimic at least some of the side effects of the real drug.
This way researchers could look directly at the role of suggestion in response to both placeboand drug. It is, however, currently considered unethical to deceive patients in this fashion.
But there is plenty of indirect evidence for Kirsch's position, including a peculiar recent finding:Both placebo response and drug response for antidepressants have steadily increased overtime, so much so that the best predictor of whether research shows positive results is the yearthe study was published. This result has yet to be explained, but Kirsch thinks it indicates theway the wide- spread publicity about antidepressants shapes patients' expectations. "It suggeststhat over time the drugs have gotten more potent for reasons other than chemistry. I wouldsuspect that it's because of increased marketing." Kirsch explains the way that marketing cancapitalize on a central mechanism of depression: "The hopelessness of depression is theexpectancy that a terrible state of affairs is not going to get better. Now you give somebody atreatment that's been touted as the cure for the worst thing in their lives. What that does is toinstill a hope, which is the opposite of depression." Kirsch's theory leads to an unsettlingconclusion: Drug com- panies may have marketed their antidepressants beyond what statistics justify, but the barrage of advertising may also have inadvertently amplified the placebo effectand thus increased the effectiveness of the drugs they are selling.
WHEN I FILL OUT A treatment report explaining to an insurance company why they ought to pay
for someone's therapy, I am asked for a diagnosis. If the patient is depressed and not on
antidepressants, I often must explain why not. Were it not for these bureaucratic demands -- and
for all the miracle-drug testimony found in advertising and casual talk -- the FDA statistics would
hardly be surprising or disturbing, because, like many clinicians, I have come to see that the
effects of Prozac and its cousins are just about as pallid as those numbers would predict: The
drugs are not panaceas, not solid evidence that depression is a chemical imbalance, but have
proved to be moderately useful for some people (and moderately harmful to others). No scientist
doubts the existence of the disconnect between the data and the way antidepressants are
perceived and used, but Kirsch's theory about it is far from the industry standard. Indeed, some
simply dismiss it out of hand -- like Donald Klein, a renowned psychiatry professor at Columbia
University's New York State Psychiatric Institute, who thinks that Kirsch's work is so biased
against antidepressants that, though asked, he declined to be among the respondents to "The
Emperor's New Drugs" -- "for the same reason," he told me, "that I don't argue with creationists."
Klein, who has conducted antidepressant trials for pharmaceutical companies, acknowledges
that the data can leave the impression that the drugs don't work very well. But he is among those
who think this says more about the trials than the drugs. According to Klein, the FDA standard --
two successful trials without untoward side ef- fects -- won't elicit a full body of knowledge about
new drugs, and may even limit what the tests can tell us. "The job of the pharmaceutical
company is to get FDA approval," he says. "So you want to go in with a dose which is effective
but doesn't create side effects. It's a real problem. Drugs are not being tested for their optimum
efficacy." Nor, given this strategy, are they tested for their maximum side effects -- which may be
why reports of agitation and suicidal impulses in excess of what the trials found have dogged the
Prozac generation of antidepressants since they were introduced.
Clinical trials can become a game for drug companies to win rather than a venue for generatingscientific knowledge. And it's a game that establishes perverse incentives, in part because drugs'limited patent lives -- usually 20 years -- begin before clinical trials, which can take a decade,start. "We're talking real money here," says Klein, noting it takes between $300 to $500 million todevelop a new drug. Klein told me that within the industry the clinical trial period is thought tocost "a million dollars a day. That adds some pressure for finishing trials fast." Despite the bottom-line approach, "there are lots and lots of compounds that get evaluated andnever approved," notes Lawrence Price, a psychiatrist who directs research at BrownUniversity's Butler Hospital. A more nuanced criterion for a successful trial is possible, but, saysPrice, "it would just take forever. It's not that there aren't important questions, but you would getso bogged down in trying to nail down the details that you would just never make any progresswith newer compounds." You also might not make any progress if you waited around for severely depressed people to
test drugs on. "The problem with antidepressant studies," according to Klein, "is that anything
that can be confused with ordinary unhappiness gets in" -- which means that subjects in clinical
trials are insufficiently depressed, too close to normal to show dramatic improvement. Price, who
has conducted clinical trials of antidepressants for 25 years, points out that recruitment
techniques like the one that attracted Janis Schonfeld to UCLA can lead to a skewed sample. "If
you go out and advertise in the newspaper for depressed people," says Price, "you are going to
get less ill people than if you are taking people who are brought in via the emergency room."
Relatively high-functioning, moderately depressed people, those most likely to enroll in and finisha trial, are, as it happens, more likely to register a high placebo response. There are nobiochemical markers of depression, no blood test or X-ray that confirms its presence, so it can bejudged only by its appearance -- which means, in trials, by the Hamilton, a test of subjectivestates scored by clinicians whose employers are paid up to $10,000 for each patient whocompletes a study. "If the investigator has directed his/her research assistant to rate liberally onthe Hamilton," says Price, "then you are going to have more people meeting the entry criterion,"typically, at least 17 points -- the line dividing mildly and moderately depressed. (One of Price'scolleagues estimates that Hamilton scores are inflated by up to five points for clinical trials.) The drug companies, of course, want more than speedy trials. They want successful ones.
"Placebo is a killer for them," Price explains, "because if they spend $40 million on a trial and geta placebo response rate of 50 percent, then they've just wasted that $40 million. There's a hugeinterest in trying to address the high placebo response rate in depression. How can it belowered? How can you identify the sample of people in whom these compounds are really goingto work?" The study in which Janis Schonfeld enrolled may provide some answers to these questions --
although somewhat inadvertently. Hoping to eliminate the trial-and-error method used to match
patients with antidepressants, the UCLA doctors were using electroencephalograms to
determine if there was some neurochemical difference between the brains of people who
respond to Effexor and those who respond to Prozac. The researchers found the differences
they were looking for, but they also got a surprise.The EEGs of placebo responders were
different from those of the drug responders, and similar to each other, a phenomenon that had
never before been observed and that may be the first step to identifying the neurochemistry of
the placebo response. This was welcome news to the drug companies, who'd like nothing more
than to eliminate placebo responders from their studies.
Take away the people most likely to show a strong placebo effect, include the people most likelyto respond to a drug, and the statistics become more favorable for the manufacturers andprovide less ammunition for critics like Greenberg and Kirsch. Psychologist David Antonuccio, aprofessor at the University of Nevada, claims that the deck is already stacked. In addition topublication bias, inflated Hamilton scores, and broken blinds, he points to the placebo washoutperiod that starts every clinical trial: All patients are given a week of placebo treatment, and thestrongest responders are eliminated from the study. The idea, of course, is to get a moreaccurate estimate of the true drug effect, but "if you put everybody on an antidepressant andwashed out everyone who responds, people would say, 'That's a very biased strategy againstthe drugs.' Well, I believe we have a strategy here that's biased against the placebo condition." AFTER JANIS SCHONFELD was debriefed, she was given her reward for participating in thestudy: a one-year supply of Effexor. She didn't consider not taking the drug. "They told me thatI'd gotten a good start, that if I'd done well on placebo, I'd probably do better on the drug." And soshe did. "After about a week or maybe two weeks it was like a fog was lifted from my eyes. Irealized I had spent much of the last 20 years in that fog." Schonfeld took Effexor for two and ahalf years and then "one day I just thought, 'You know, I don't think I need this medicationanymore.' I spent three weeks weaning off of it. That was about a year and a half ago, and Ihaven't really felt that I needed it since." She emphatically rules out the possibility that herimprovement was a result of placebo effects, amplified or otherwise.
To Kirsch, Schonfeld's is a case of lost opportunity. "Why not say to her, 'You did this'? Peoplerespond the way they were expecting to respond, so why not work on that expectation? Why not teach her the strategies that she can use to make herself feel better?" Antonuccio says,"Placebo is a valid intervention in and of itself," adding that people like Schonfeld have amplecontact with trained staff during trials, which may itself be what accounts for the high placeborates. "It's possible that psychological treatments are mostly placebo as well," he says -- not, ashe is quick to add, that there's any- thing wrong with that. "We just ought not to see the placeboeffect as some sort of inferior response or condition." But even though, as Kirsch notes, "more placebos have been administered to researchparticipants than any single experimental drug," they remain poorly understood and used, for themost part, only inadvertently and haphazardly. The discovery of biological underpinnings of theplacebo effect may change this, as drug researchers grasp the potential of turning yet anotherneurochemical pathway into a pharmaceutical market by developing a placebo drug. Bizarre asthis sounds, it may be the only incentive that will lead a profit-driven health care industry towardan understanding of humanity's oldest means of healing.
Journal of Basic and Applied Advances in Sciences Vol. 4, No. 1 (2016), 34-38 Effect of memory improvement by a cholinergic agonist on morphine-conditioned place preference in mice Department of Biology, Fars Science and Research Branch, Fars, Iran Abstract This research aims at studying the effect of memory improvement by a cholinergic agonist ,donepezil, on creating morphine dependence in mice using conditioned place preference(CPP) method.The donepezil was dissolved in distilled water and was administered subcutaneously at a dose of 2.5 mg/kg. The mice received 10 mg/kg morphine subcutaneously. In the conditioning stage that lasted for 8 days, different groups of mice, after receiving the treatment were randomly placed in compartment for 30 minutes. The post-conditioning stage included the fourth, the ninth days ( that is a 24h after the last session), the twelfth day ( that is 96h after the last session) and the sixteenth day ( that is a 192h after the last session).The results showed a significant decrease (p≤0.05) in the place preference of morphine+donepezil group compared with the morphine group.This last for eight days after quitting the use of this drug.According to the results of study, donepezil through Ach increase ,inhibits the activity of dopaminergic neurons and reduces the morphine-addiction. Keywords: Memory, cholinergic agonist, morphine, donepezil, CPP, mice