21세기는 과연 치매시대(痴呆時代 The Age of Alzheimers)인가?

 

뉴욕 타임스 2010 10 28

 

산드라 오코너(Sandra Day OConner), 스탠리 푸루시너(Stanley Prusiner) and 켄 디히트발트(Ken Dychtwald)

강성종 번역

譯者註釋: 21세기는 과연 치매(痴呆)의 시대인가? 벌써 지난 20년간 많은 연구와 신약개발에 정력을 쏟아 부었지만 아무런 진전을 보이지 못하고있다. 이 글에 앞서 지난 8월 28일 뉴욕 타임스는 치매에 관해서 슬픈 기사를 또 하나 썼다. 여지것 연구는 허사였고 이제 시작이라는것이다. 문헌: Years Later, No Magic Bullet Against Alzheimer’s Disease  http://nyti.ms/9OR5E0 다음 글은 슬픈 이야기로 정부가 돈을 많이 써야하는 것 밖에 방법이 없다는 것이다. 이 글을 번역한 筆者는 오래동안 바로 이 치매를 연구해온 뇌 과학자이다. 지난 40년간의 경험으로 볼때 치매(痴呆)는 치료 가능한 병이다. 그래서 필자는 뉴욕의 Biodyne Corporation의 Axon Laboratories 에서 치매 약을 설계, 개발하고 있다. 치매 치료약과 더불어 우울증 치료약을 동시에 개발하고 있는 필자에겐 아마도 이 연구의 성공적인 결과가 사회에 공헌하는 생애의 마지막 일이 될 거라고 생각하고 있다. 치매에 관해서 좀 더 알고 싶은 분들은 < 강성종 저, 당신의 두뇌, 안녕하십니까? 라이프 사이언스, 서울 2008> 을 참조하기 바란다.
강성종

출처: http://www.nytimes.com/2010/10/28/opinion/28oconnor.html?nl=opinion&emc=tya1

 

원문 번역

 

미국정부는 미국인의 건강에 가장 위협적인 병이 되고 있는 치매를 등한시(等閑視)하고 있다. 현재까지 치매는 100% 불치의 병이며 100% 치명적인 병이다. 이 병은 부자나 가난한 사람이나, 藍領階層(blue-collar)이나 白領階層(white-collar)나 남녀를 막론하고,  당사자가 누구인지 관계하지 않고 공격한다. 퇴행성 질환인 이병은 환자의 기억, 판단, 존엄성을 송두리째 갉아먹고 자신마저 돌볼 줄 모르게 방치되어 뇌를 파괴하며, 결국 자기가 누구인지도 모르게 자기존재를 파괴한다. 그리고 감성적으로나 재정적으로 종종 환자의 보호자나 가족들을 고사시키고 있다.

                                                     Anthony Russo for New York Times



오는 정월1일부터 79백만 명 이상의
영아조 세대(嬰兒潮 世代 baby boom generation)가  매 8초마다 65세 이상이 된다. 이 말은 매일 만 명씩, 1년에 4백만 명씩 65세를 넘긴다는 뜻이다. 이들은 앞으로 19년 동안 증가하는 치매의 위험성에 부딪치게 된다. 이 병의 증세나 다른 형태의 치매 증상도 중년 전에는 보이지 않다가 증세가 나타나기 시작하면서 매 5년마다 倍加된다. 현재 미국 인구가 급속도로 증가하고 있긴 하지만, 85세 이상의 사람들 중 두 명에 한 명꼴로 치매에 걸리고 있다. 이는 현재 5백만명이 치매환자이며, 2050년까지 천35십만의 미국인이 치매에 걸린다고 예측할 수 있다.

 

1961년 존 F. 케네디 대통령이 60년대 말까지는 미국이 달나라에 사람을 보내겠다는 계획에공헌한 것처럼 우리는 2020년까지 치매를 중지할 계획을 세워야 한다. 우리의 공동체의 미래를 구제하기 위해서, 우리는 충분한 자원과 과학적 재능과 문제를 해결하는 기술을 총 동원해야 한다.

 

오늘날 우리의 입장을 경제적으로 분석해보면 국가보건원(NIH) 1錢을 치매연구에 사용하고 있으며 치매환자를 보살피는데 3.5달러를 사용하고 있다. 이것은 적절한 연구를 하지 않는데도 불구하고 재정비용이 많이 들고 있음을 보여주고 있다. 현재 미국은 치매환자를 보살피는일에 천720억 불을 사용하고 있으며 2020년에는 2조 불이 되고 2050년에는 50조 불로 늘어난다.

 

우리가 지금 치매환자의 발병을 5년만 늦춘다고 해도 미국에 있는 치매요양원의 많은 입원실이 텅 비게 될 것이다. 요나스 살크(Jonas Salk) 박사가 그가 개발한 역묘(疫苗 vaccine)로 소아마비를 전부 없앤 것처럼 우리가 치매를 전부 없앨 수 있다면, 모든 미국사람들의 건강과 장수, 생산적인 삶을 누릴 수 있는 가능성을 높일 뿐만 아니라 수조원의 달러를 절약할 수가 있는 것이다.

 

경험에 의하면 정기적 건강 검진이나 건강에 도움이 되는 여러 관련 부분에 참여한다든가,
아니면 체육관이나
종횡전자자미(縱橫填字字謎 crossword puzzles)를 채운다든가 하는 연습을 함으로서 치매를 방지할 수가 있다. 로날드 레간 미 대통령은 사랑하는 가족의 보살핌과 그의 특별한 업무의 자극, 그리고 의료진의 관리와 육체적 운동을 했음에도 불구하고 10년 이상 치매로 고생을 했다. 이제 우리에게 필요한 것은 병의 원인을 직접 공격하는 새로운 약밖에 없다.

 

지금까지 몇 개 되지 않는 치매 치료 약만이 미국 식품 의약청(FDA)에서 승인 되었지만 이는 건망증(forgetfulness), 定向障碍(disorientation), 혼돈(confusion)과 같은 증세를 호전하는 정도이다.  그 어떤 약도 근본적으로 퇴행성 뇌질환을 지연시키지 못한다.

 

1980년 중반 에이즈(AIDS)를 퇴치하기 위한 각오를 하고 약 10년의 지속적인 투자와 백억 달러의 투자가 이루어져서야  에이즈(AIDS)를 항 역전록매병독료법抗逆轉錄酶病毒療法(antiretroviral therapies)으로 치료 가능하게 했다. 이 약은 미국경제에 1.4조 달러를 절약해준 셈이다. 국가보건연구소는 에이즈(AIDS)연구에 매년 30억 달러 씩 투자한다. 반면, 치매는 에이즈 보다 5배 이상의 환자가 있음에도 불구하고 겨우 469백만 달러를 지원한다.

 

치매를 연구하는 대부분의 의약 연구가들은 효율적인 약을 개발하기 위해서는 우선 무엇이 이 질병과 연관이 되어 있는지를 이해해야 한다는데 동의한다. 그들은 두뇌에서 생기는 기이단백(奇異蛋白)이 이 병과 어떻게 관계가 있는지를 찾아야 한다. 이들 연구가들은 치매가 진행하는 과정을 알 수 있는모형이 필요하다고 한다. 그래야 표적 치료약을 찾을 수가 있기 때문이다. 그리고 궁극적으로 혈관에서 두뇌로 어떻게 운반하는가를 알아야 한다.

 

2020년쯤에는 잘 설계되고 적절한 재정이 뒷바침된 국가적 전략 계획으로 치매 약의 돌파구를 찾을 수 있을 것으로 믿는다. 의회는 그 전에 치매연구에 년 20억 달러의 연방정부의 투자를 가능하게 하는 입법안 부터 만들어야 한다. 그리고 대통령은 치매에 대한 전략을 개발하고 수행하는 관리처를 선정해야 한다. 입법부가 이 법안을 이번 파각압회의(跛腳鴨會議 lame-duck session)에서 통과시킬 수 있다면 2020년 목표를 달성할 수 있는 진지한 첫발을 디디는 샘이 될 것이다.

 

많은 과학가들은 치매를 상한증(傷寒症 typhoid)이나 소아마비(polio) 나 많은 소아암(childhood cancers)과 같은 병의 목록에 집어 넣으려고 한다. 그러나 우리가 지금 당장 연구를 하지 않는다면 영아조 세대(婴兒潮世代 baby boomers) 가 그 혜택을 보기에는 너무 늦다. 미국의 노화가 승리로 갈 것인가 비극으로 끝날 것인가의 문제는, 과연 이 가공할 질병과의 싸움에서 치매가 우리를 쓰러 뜨리기 전에 이 질병을 무찔러 낼 수 있는가 하는 능력에 달려 있는 것이다.

 
(주)

산드라 오코너(Sandra Day OConnor)는 치매환자인 남편을 돌보기 위해서 평생직장인 대법관 자리를 사임한바 있다. 자세한 얘기는 <강성종 저, 당신의 두뇌 안녕하십니까,  라이프 사이언스, 서울 2008) 7장에 치매와 함께 잘 설명되어있다. 스탠리 푸루시너(Stanley Prusiner)는 노벨 의학상 수상자로 현재 UCSF 교수. 퇴행성 뇌질환 연구소 소장으로 근무한다. 켄 디히트발트(Ken Dychtwald)는 심리학과 노인학가로서 노화하는 세계인구에 관하여 기업을 자문하는 회사의 CEO이다.

 

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AARP Logo

Do Antidepressants Work?

A leading expert talks about the latest research on these drugs

Do antidepressant medications work? The question may seem an odd one to ask these days. More than one in 10 Americans have prescriptions for antidepressants, which rake in sales of almost $10 billion in the United States alone. Yet for years, researchers have questioned whether the intensively advertised drugs are truly effective. One of the first to cast doubt was psychologist Irving Kirsch, professor emeritus at the University of Connecticut and now a professor of psychology at the University of Hull in England. Widely regarded as one of the world’s leading experts on psychiatric drugs and the placebo effect, he is the author of The Emperor’s New Drugs, as well as more than 200 research papers.

The AARP Bulletin reached Kirsch at home in England to discuss his findings and the controversy they’ve sparked.

Q. Your studies suggest that antidepressants are no more effective than sugar pills, or placebos. How can that be?

A. Placebo effect is very powerful when you’re treating depression. Placebos offer hope. And one of the chief features of depressions is a sense of hopelessness, the belief that you’re not going to get better. Anything that instills a sense of hope will at least temporarily help treat depression. Our studies show that placebos are about 80 percent effective, which is exactly how effective antidepressants are in the short-term.

Q. But aren’t the newest generation of antidepressants designed to restore normal levels of serotonin in the brain?

A. The theory behind drugs such as Prozac and Paxil, which are selective serotonin re-uptake inhibitors, or SSRIs, is that depression is linked to low levels of serotonin. But most researchers have abandoned that theory. One reason is that the newest drugs are just about as effective as older drugs that don’t affect serotonin levels. In fact, a new antidepressant recently approved in France is a selective serotonin re-uptake enhancer. It has the opposite effect of drugs like Paxil or Prozac. And yet it appears to work just as well. That tells us the serotonin theory is wrong.

Q. Published in January in the Journal of the American Medical Association, a major study also cast doubt on the effectiveness of antidepressants. Does it add anything to the debate?

A. Yes. The conclusions of that study, led by researchers from the University of Pennsylvania, are almost exactly what we found. But the JAMA study is based on a completely different set of data. The fact that it came to the same conclusion shows that the findings are robust. All in all, this new study confirms and updates our conclusions.

Q. Obviously, these findings are controversial. Many doctors who prescribe antidepressants insist that they see benefits in their patients. Are they wrong?

A. Their perception is entirely right. People do get better on antidepressants. And they get better on placebos. But doctors don’t prescribe sugar pills. They prescribe medications. And when they see patients getting better, they naturally attribute that to the drug. They can’t compare antidepressants to placebos in their practices. They have no way of knowing how much of the benefit is placebo effect and how much is a chemical effect. For that, you do research.

Q. What’s the bottom line from your studies?

A. Antidepressants at best have a small and clinically insignificant effect for mild, moderate and even severe depression. The drugs may be slightly more effective than placebo for people with very severe depression, at the far end of the scale. But even that small difference may be a placebo effect.

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 AARP Logo

Treatments that help older adults.

Photo by Larry Sultan/Gallery Stock

“It is the aloneness within us made manifest,” Andrew Solomon wrote in his book The Noonday Demon: An Atlas of Depression, “and it destroys not only connection to others but also the ability to be peacefully alone with oneself.”

Depression is the most common of all mental illnesses, afflicting an estimated 7 percent of the population. More than one in 10 Americans have prescriptions for antidepressants, now among the most widely used of all medications. But some doctors are questioning the efficacy of these drugs in treating depression. And even with new advances in understanding depression, many cases still go undiagnosed and untreated, experts say—especially among older people.

The depression debate

Many researchers now believe that depression is caused by chemical imbalances in the brain. A predisposition to depression is known to run in families, and there’s also evidence that traumas, certain illnesses and childhood abuse can lead to depression later in life.

For all that is known about depression, however, there’s still plenty of debate about how best to diagnose and treat it.

The most recent furor was sparked by a report published in January in the Journal of the American Medical Association. A team led by psychologist Jay Fournier of the University of Pennsylvania, evaluating data from several studies, concluded that antidepressants, despite their popularity, are no more effective than sugar pills for most people with mild or moderate depression. For severe forms of the disease, the pills do help, the scientists acknowledged. Still, they’re far from a cure-all.

Irving Kirsch, professor emeritus at the University of Connecticut and a professor of psychology at the University of Hull in England, who is widely regarded as one of the world’s leading experts on psychiatric drugs and the placebo effect, says this latest study reinforces earlier findings: “Our studies show that placebos are about 80 percent effective, which is exactly how effective antidepressants are in the short term.”

But, he adds, the “placebo effect is very powerful when you’re treating depression. Placebos offer hope. And one of the chief features of depression is a sense of hopelessness, the belief that you’re not going to get better.” Anything that instills a sense of hope, he says, “will at least temporarily help treat depression.”

For researchers, the placebo effect makes evaluating the effectiveness of mood-altering drugs even more complicated. There is no objective test for depression, as there is for high cholesterol or elevated blood pressure. The only way to gauge if antidepressants are working is to ask people how they’re feeling.

Still, plenty of experts—including many psychiatrists—insist that the widely used medications do work. “We know from years of clinical experience that these medications help people who are moderately or severely depressed,” says Gary Small, M.D., professor of psychiatry at the David Geffen School of Medicine at UCLA and director of the UCLA Center on Aging.

One reason their effectiveness may not be captured in studies, he explains, is that a medication that works for one patient may not work for another. “We often find that we have to try several different medications before we find the one that works for a particular patient.” Unfortunately, doctors have no way to know in advance which antidepressant is likely to help.

The pills also require time to take effect—up to six weeks in some patients. “So one problem we often see is that people start taking antidepressants. Then, when they don’t feel better right away, they stop, thinking the pills aren’t working,” he says.

In fact, antidepressants can be effective, many doctors contend, and most prescribe them as the first-line treatment. For older patients, who are often on other medications that may interact with the antidepressants, doctors typically begin with small doses and increase as needed.

Depression linked to physical ills in older people

“Serious depression can ruin people’s lives and destroy families,” says Small.

But a reliable definition of depression is difficult in part because it takes many forms. “Depression is often associated with persistent sadness and melancholy, but sadness isn’t always part of it,” says Susan W. Lehmann, M.D., assistant professor in the department of psychiatry and behavioral sciences at the Johns Hopkins School of Medicine. “The symptoms of depression can also be a loss of pleasure and enjoyment in the things people used to enjoy, or a change in one’s sense of oneself, a feeling of worthlessness and uselessness, a kind of blankness.”

In older people, depression frequently shows up not as sadness but as a constellation of physical complaints—one of several reasons it is frequently overlooked.

“Older patients come in saying, ‘I can’t sleep, nothing tastes good, my back hurts,’ ” says Small. “The physical complaints may be real, but the underlying problem is depression. When we treat the depression, the physical complaints improve.”

Thoughts of suicide, one of the hallmarks of severe depression, also take a different, more passive form in older people, says Small. “Instead of someone saying, ‘Yes, I’ve thought of killing myself,’ they might say, ‘If God took me now, I wouldn’t mind.’ ”

Depression in older people may be accepted because younger family members tend to assume it’s an inevitable part of growing old, says Lehmann. “There’s a tendency to think, ‘No wonder Grandpa is depressed. I’d be depressed if I had to give up driving, or use a walker, or was losing my vision.’ ”

It’s not inevitable

In reality, the vast majority of older people go through life’s ups and downs without suffering depression. Depression isn’t a part of normal aging, experts insist.

When depression strikes, however, it can affect not only mental but also physical health. Being diagnosed with any serious illness can lead to depression, says Lehmann. “One-third of people who have had a stroke go on to develop depression, for example. Forty percent of people with Parkinson’s develop depression.”

Depression, in turn, can make these diseases worse. “Studies show that depression slows recovery from a heart attack or hip or knee replacement surgery,” says Lehmann. “When people with diabetes are depressed, their blood sugar is less well controlled.”

Depression also can aggravate symptoms of memory loss and dementia. “So depression is really a double or a triple whammy for older people who are dealing with serious medical conditions,” says Lehmann.

Finding a way out

Of course, when patients are mired in severe depression, all they want is some relief.

The first step is seeking help. The symptoms of severe depression are usually obvious. Overwhelmed by feelings of hopelessness, sufferers find themselves unable to manage even the simplest daily activities.

The distinction between moderate depression and garden-variety sadness over the loss of a job or a troubled marriage is less clear-cut. One clue, says Lehmann, is how persistent the sadness or hopelessness is. “Even if something really tough has happened, most people can be distracted or cheered up for a short period of time. That’s often not true when people are suffering depression.”

Perhaps the best indication that it’s time to seek help is when persistent changes in mood get in the way of everyday life. “Anytime someone begins to have problems carrying out the basic activities of daily life—managing money, putting meals together, going to church—it’s worth talking to a doctor,” says Lehmann.

A variety of psychotherapeutic approaches have also been shown to help. Indeed, a combination of drug treatment and counseling may offer the best chance of banishing the shadows of depression for good. Psychotherapy takes many forms, from addressing relationship problems that may be causing distress to practicing ways to counter negative thoughts. Research suggests that techniques such as these may have long-lasting results, reducing the risk that depression will return.

“The important message to get out there is that people do get better,” says Small. “Depression may feel hopeless, but it isn’t.”

Peter Jaret is a freelance health writer in Petaluma, Calif., and the author of Nurse: A World of Care.

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Newsweek

Combat Stress System to Come Under New Focus

Amid the patrols, searches, training of Iraqi counterparts and the usual tedium of soldiering, many U.S. troops in Iraq are also trying to manage their mental health. Modern warfare today means an Army in which sleeping pills and anti-depressants are dispensed by medical units to help keep troops functioning in a war in which the forces are stretched thin. It’s not uncommon, Army psychologists have said, for soldiers to threaten others or themselves. There are procedures, like confiscating weapons and imposing around-the-clock suicide watches, to prevent danger. Now the shocking shooting spree by a U.S. soldier who killed five of his comrades at a combat stress center is placing new emphasis on the military mental health system, and the challenges of convincing some soldiers to use it.

The Pentagon today announced that the soldier, Sgt. John M. Russell is in custody facing a charge of aggravated assault and five counts of murder. After being flagged by commanders for stress problems about a week ago, the military said, Russell was ordered to a combat stress clinic at Camp Liberty (abutting his home base, Camp Victory). His weapon had already been taken from him. According to published reports, he apparently had an altercation with someone there and used another person&apos;s gun to kill two officers who were staff members in the clinic and three soldiers who happened to be there at the time. It’s the worst reported case of a soldier attacking his own troops since the war started. In addition to the criminal investigation, the Army has ordered a complete review of its mental health system.

The mental health infrastructure in Iraq has been growing throughout the war. The shooting yesterday took place at one of four “restoration centers” in Iraq, where soldiers can bunk temporarily or get outpatient care along with therapy. There are about 40 other combat stress teams on location with troops around the country. Their phone numbers are posted on bulletin boards, handed out by chaplains and commanders. But commanders acknowledge the system has problems, different doctrines and techniques have been tried.

As an Army psychologist explained to me a few years ago, there are competing interests between mental health and war fighting. One of the biggest is that soldiers and officers still look at therapy as a sign of weakness. Secondly, the goal is “unit cohesion,” that is, keeping the soldier at work rather than sending him or her home. Medicines can be prescribed but, as soldiers are sent back to the field, they don’t have the follow-up they need to monitor their condition--or make sure they don’t hand out the pills to others.

The hope for the troop was that as the violence in Iraq subsided and tours of duty were shortened, stress would decrease. But in some cases, simply being connected through the Internet to family back home has been enough to cause problems--the psychiatrist told me of one case in which a wife back home had posted photos of her and her new boyfriend on the Web to torment her soldier husband. And a recent USA Today story posited that boredom may increase stress.

The psychiatrist told me that it was especially hard to get officers to seek help because they feared it would impede their career or undermine their reputations. He tried to argue that it would help them avoid career-ruining incidents. The words seemed apt today as Maj. Gen. Daniel P. Bolger talked about the military’s efforts to get people to go for help. “It’s particularly challenging for a fellow like Sgt. Russell. He’s a non-commissioned officer,” Bolger said. “He’s in a leadership capacity and to make that trip down there is a tough decision for him or his chain of command to make, but we’re willing to make it.”


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Newsweek

Window on the Mind: Will the Antidepressant Work?

Bad enough that antidepressants fail to help an estimated one-third of people suffering from depression. Even worse is that it can take 6 to 8 weeks before that becomes clear: the patient dutifully swallows Zoloft after Zoloft or Paxil after Paxil, only to find after two months that she is no better off—at which point her doctor typically puts her on a different med, and the whole process of trial-and-error starts all over again. There’s got to be a better way—and now there may be.

Last September I wrote about a new use of EEGs—the decades-old technology that measures brain waves—in which psychiatrists compare the EEG of a patient to thousands of EEGs in a huge database that matches it to an effective treatment. (This is different from using EEGs to diagnose a mental illness, something that doesn’t seem to work, perhaps because there are many, many ways for a brain to have an underlying pattern of electrical activity that adds up to “depression” or “bipolar disorder” or other psychiatric disease.) CNS Response, the California company that runs the database, looks for matches between EEG and effective drug. In about 75% of cases, that produces surprising pairings—such as an anticonvulsive drug for a patient with depression—that the physician would never have thought of.

A new study being reported this afternoon at the annual meeting of the American Psychiatric Association finds another use for EEGs: predicting which patients will respond to the antidepressant they have just started. Rather than waiting for months, patients suffering from major depression—as nearly 15 million Americans do—take the drug for a week and then undergo an EEG (which is painless, noninvasive and relatively cheap, on the order of $150).

The study, led by Andrew Leuchter of UCLA and called BRITE (Biomarkers for Rapid Identification of Treatment Effectiveness), had 73 patients take the antidepressant escitalopram, which is sold as Lexapro and belongs to same category—selective serotonin reuptake inhibitors, or SSRIs—as Prozac and many others. That’s the quandary: all of the drugs supposedly work by targeting the brain’s serotonin system (which is actually a questionable claim, but that’s a story for another day), so which one will help a particular patient? Before starting the drug and again after taking it for 48 hours, for one week, and for two and seven weeks, the patients underwent EEGs. At the one-week visit, doctors assessed how well they were responding to the drug; the researchers also identified genetic markers that have been reported to predict how well patients will respond to SSRIs, and measured how much of the drug was in the patients’ blood, which is thought to be an indication of whether it is likely to work.

The bad news: the docs were terrible at predicting, based on how well the patients were doing after a week on Lexapro, whether the drug would alleviate their depression. The genetic markers fared no better. Neither did the blood levels.

But of the 38 patients who got a little better and the 28 who recovered completely by the end of the seven weeks, the EEG readings—measuring brain-wave changes after one week on the drug—did pretty well, predicting who would get a little better or even recover with 74% accuracy (compared to 51% accuracy for the docs’ evaluation).

“Early changes in frontal EEG signals carry important information about future clinical response,” Leuchter said in a statement, suggesting that EEGs have “the potential to help clinicians improve the care of patients suffering from depression.”

Caveats: the company that sells the EEG system, Aspect Medical Systems, funded the study, and Leuchter has been a paid consultant to Aspect, served on its board and received grant money from Aspect. (I have blogged before on how company-funded studies can be skewed.) And seven weeks is not exactly long-term. Still, anything that moves us beyond the current hit-and-miss approach to treating depression is to be welcomed.


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Newsweek

The Depressing News About Antidepressants

Studies suggest that the popular drugs are no more effective than a placebo. In fact, they may be worse.

Although the year is young, it has already brought my first moral dilemma. In early January a friend mentioned that his New Year's resolution was to beat his chronic depression once and for all. Over the years he had tried a medicine chest's worth of antidepressants, but none had really helped in any enduring way, and when the side effects became so unpleasant that he stopped taking them, the withdrawal symptoms (cramps, dizziness, headaches) were torture. Did I know of any research that might help him decide whether a new antidepressant his doctor recommended might finally lift his chronic darkness at noon?

The moral dilemma was this: oh, yes, I knew of 20-plus years of research on antidepressants, from the old tricyclics to the newer selective serotonin reuptake inhibitors (SSRIs) that target serotonin (Zoloft, Paxil, and the granddaddy of them all, Prozac, as well as their generic descendants) to even newer ones that also target norepinephrine (Effexor, Wellbutrin). The research had shown that antidepressants help about three quarters of people with depression who take them, a consistent finding that serves as the basis for the oft-repeated mantra "There is no question that the safety and efficacy of antidepressants rest on solid scientific evidence," as psychiatry professor Richard Friedman of Weill Cornell Medical College recently wrote in The New York Times. But ever since a seminal study in 1998, whose findings were reinforced by landmark research in The Journal of the American Medical Association last month, that evidence has come with a big asterisk. Yes, the drugs are effective, in that they lift depression in most patients. But that benefit is hardly more than what patients get when they, unknowingly and as part of a study, take a dummy pill—a placebo. As more and more scientists who study depression and the drugs that treat it are concluding, that suggests that antidepressants are basically expensive Tic Tacs.

Hence the moral dilemma. The placebo effect—that is, a medical benefit you get from an inert pill or other sham treatment—rests on the holy trinity of belief, expectation, and hope. But telling someone with depression who is being helped by antidepressants, or who (like my friend) hopes to be helped, threatens to topple the whole house of cards. Explain that it's all in their heads, that the reason they're benefiting is the same reason why Disney's Dumbo could initially fly only with a feather clutched in his trunk—believing makes it so—and the magic dissipates like fairy dust in a windstorm. So rather than tell my friend all this, I chickened out. Sure, I said, there's lots of research showing that a new kind of antidepressant might help you. Come, let me show you the studies on PubMed.

It seems I am not alone in having moral qualms about blowing the whistle on antidepressants. That first analysis, in 1998, examined 38 manufacturer-sponsored studies involving just over 3,000 depressed patients. The authors, psychology researchers Irving Kirsch and Guy Sapirstein of the University of Connecticut, saw—as everyone else had—that patients did improve, often substantially, on SSRIs, tricyclics, and even MAO inhibitors, a class of antidepressants that dates from the 1950s. This improvement, demonstrated in scores of clinical trials, is the basis for the ubiquitous claim that antidepressants work. But when Kirsch compared the improvement in patients taking the drugs with the improvement in those taking dummy pills—clinical trials typically compare an experimental drug with a placebo—he saw that the difference was minuscule. Patients on a placebo improved about 75 percent as much as those on drugs. Put another way, three quarters of the benefit from antidepressants seems to be a placebo effect. "We wondered, what's going on?" recalls Kirsch, who is now at the University of Hull in England. "These are supposed to be wonder drugs and have huge effects."

The study's impact? The number of Americans taking antidepressants doubled in a decade, from 13.3 million in 1996 to 27 million in 2005.

To be sure, the drugs have helped tens of millions of people, and Kirsch certainly does not advocate that patients suffering from depression stop taking the drugs. On the contrary. But they are not necessarily the best first choice. Psychotherapy, for instance, works for moderate, severe, and even very severe depression. And although for some patients, psychotherapy in combination with an initial course of prescription antidepressants works even better, the question is, how do the drugs work? Kirsch's study and, now, others conclude that the lion's share of the drugs' effect comes from the fact that patients expect to be helped by them, and not from any direct chemical action on the brain, especially for anything short of very severe depression.

As the inexorable rise in the use of antidepressants suggests, that conclusion can't hold a candle to the simplistic "antidepressants work!" (unstated corollary: "but don't ask how") message. Part of the resistance to Kirsch's findings has been due to his less-than-retiring nature. He didn't win many friends with the cheeky title of the paper, "Listening to Prozac but Hearing Placebo." Nor did it inspire confidence that the editors of the journal Prevention & Treatment ran a warning with his paper, saying it used meta-analysis "controversially." Al-though some of the six invited commentaries agreed with Kirsch, others were scathing, accusing him of bias and saying the studies he analyzed were flawed (an odd charge for defenders of antidepressants, since the studies were the basis for the Food and Drug Administration's approval of the drugs). One criticism, however, could not be refuted: Kirsch had analyzed only some studies of antidepressants. Maybe if he included them all, the drugs would emerge head and shoulders superior to placebos.

Kirsch agreed. Out of the blue, he received a letter from Thomas Moore, who was then a health-policy analyst at George Washington University. You could expand your data set, Moore wrote, by including everything drug companies sent to the FDA—published studies, like those analyzed in "Hearing Placebo," but also unpublished studies. In 1998 Moore used the Freedom of Information Act to pry such data from the FDA. The total came to 47 company-sponsored studies—on Prozac, Paxil, Zoloft, Effexor, Serzone, and Celexa—that Kirsch and colleagues then pored over. (As an aside, it turned out that about 40 percent of the clinical trials had never been published. That is significantly higher than for other classes of drugs, says Lisa Bero of the University of California, San Francisco; overall, 22 percent of clinical trials of drugs are not published. "By and large," says Kirsch, "the unpublished studies were those that had failed to show a significant benefit from taking the actual drug.") In just over half of the published and unpublished studies, he and colleagues reported in 2002, the drug alleviated depression no better than a placebo. "And the extra benefit of antidepressants was even less than we saw when we analyzed only published studies," Kirsch recalls. About 82 percent of the response to antidepressants—not the 75 percent he had calculated from examining only published studies—had also been achieved by a dummy pill.

The extra effect of real drugs wasn't much to celebrate, either. It amounted to 1.8 points on the 54-point scale doctors use to gauge the severity of depression, through questions about mood, sleep habits, and the like. Sleeping better counts as six points. Being less fidgety during the assessment is worth two points. In other words, the clinical significance of the 1.8 extra points from real drugs was underwhelming. Now Kirsch was certain. "The belief that antidepressants can cure depression chemically is simply wrong," he told me in January on the eve of the publication of his book The Emperor's New Drugs: Exploding the Anti-depressant Myth.

The 2002 study ignited a furious debate, but more and more scientists were becoming convinced that Kirsch—who had won respect for research on the placebo response and who had published scores of scientific papers—was on to something. One team of researchers wondered if antidepressants were "a triumph of marketing over science." Even defenders of antidepressants agreed that the drugs have "relatively small" effects. "Many have long been unimpressed by the magnitude of the differences observed between treatments and controls," psychology researcher Steven Hollon of Vanderbilt University and colleagues wrote—"what some of our colleagues refer to as 'the dirty little secret.' " In Britain, the agency that assesses which treatments are effective enough for the government to pay for stopped recommending antidepressants as a first-line treatment, especially for mild or moderate depression.

But if experts know that antidepressants are hardly better than placebos, few patients or doctors do. Some doctors have changed their prescribing habits, says Kirsch, but more "reacted with anger and incredulity." Understandably. For one thing, depression is a devastating, underdiagnosed, and undertreated disease. Of course doctors recoiled at the idea that such drugs might be mirages. If that were true, how were physicians supposed to help their patients?

Two other factors are at work in the widespread rejection of Kirsch's (and, now, other scientists') findings about antidepressants. First, defenders of the drugs scoff at the idea that the FDA would have approved ineffective drugs. (Simple explanation: the FDA requires two well-designed clinical trials showing a drug is more effective than a placebo. That's two, period—even if many more studies show no such effectiveness. And the size of the "more effective" doesn't much matter, as long as it is statistically significant.) Second, doctors see with their own eyes, and feel with their hearts, that the drugs lift the black cloud from many of their depressed patients. But since doctors are not exactly in the habit of prescribing dummy pills, they have no experience comparing how their patients do on them, and therefore never see that a placebo would be almost as effective as a $4 pill. "When they prescribe a treatment and it works," says Kirsch, "their natural tendency is to attribute the cure to the treatment." Hence the widespread "antidepressants work" refrain that persists to this day.

Drug companies do not dispute Kirsch's aggregate statistics. But they point out that the average is made up of some patients in whom there is a true drug effect of antidepressants and some in whom there is not. As a spokesperson for Lilly (maker of Prozac) said, "Depression is a highly individualized illness," and "not all patients respond the same way to a particular treatment." In addition, notes a spokesperson for Glaxo-Smith-Kline (maker of Paxil), the studies analyzed in the JAMA paper differ from studies GSK submitted to the FDA when it won approval for Paxil, "so it is difficult to make direct comparisons between the results. This study contributes to the extensive research that has helped to characterize the role of antidepressants," which "are an important option, in addition to counseling and lifestyle changes, for treatment of depression." A spokesperson for Pfizer, which makes Zoloft, also cited the "wealth of scientific evidence documenting [antidepressants'] effects," adding that the fact that antidepressants "commonly fail to separate from placebo" is "a fact well known by the FDA, academia, and industry." Other manufacturers pointed out that Kirsch and the JAMA authors had not studied their particular brands.

Even Kirsch's analysis, however, found that antidepressants are a little more effective than dummy pills—those 1.8 points on the depression scale. Maybe Prozac, Zoloft, Paxil, Celexa, and their cousins do have some non-placebo, chemical benefit. But the small edge of real drugs compared with placebos might not mean what it seems, Kirsch explained to me one evening from his home in Hull. Consider how research on drugs works. Patient volunteers are told they will receive either the drug or a placebo, and that neither they nor the scientists will know who is getting what. Most volunteers hope they get the drug, not the dummy pill. After taking the unknown meds for a while, some volunteers experience side effects. Bingo: a clue they're on the real drug. About 80 percent guess right, and studies show that the worse side effects a patient experiences, the more effective the drug. Patients apparently think, this drug is so strong it's making me vomit and hate sex, so it must be strong enough to lift my depression. In clinical-trial patients who figure out they're receiving the drug and not the inert pill, expectations soar.

That matters because belief in the power of a medical treatment can be self-fulfilling (that's the basis of the placebo effect). The patients who correctly guess that they're getting the real drug therefore experience a stronger placebo effect than those who get the dummy pill, experience no side effects, and are therefore disappointed. That might account for antidepressants' slight edge in effectiveness compared with a placebo, an edge that derives not from the drugs' molecules but from the hopes and expectations that patients in studies feel when they figure out they're receiving the real drug.

The boy who said the emperor had no clothes didn't endear himself to his fellow subjects, and Kirsch has fared little better. A nascent collaboration with a scientist at a medical school ended in 2002 when the scientist was warned not to submit a grant proposal with Kirsch if he ever wanted to be funded again. Four years later, another scientist wrote a paper questioning the effectiveness of antidepressants, citing Kirsch's work. It was published in a prestigious journal. That ordinarily brings accolades. Instead, his department chair dressed him down and warned him not to become too involved with Kirsch.

But the question of whether antidepressants—which in 2008 had sales of $9.6 billion in the U.S., reported the consulting firm IMS Health—have any effect other than through patients' belief in them was too important to scare researchers off. Proponents of the drugs have found themselves making weaker and weaker claims. Their last stand is that antidepressants are more effective than a placebo in patients suffering the most severe depression.

So concluded the JAMA study in January. In an analysis of six large experiments in which, as usual, depressed patients received either a placebo or an active drug, the true drug effect—that is, in addition to the placebo effect—was "nonexistent to negligible" in patients with mild, moderate, and even severe depression. Only in patients with very severe symptoms (scoring 23 or above on the standard scale) was there a statistically significant drug benefit. Such patients account for about 13 percent of people with depression. "Most people don't need an active drug," says Vanderbilt's Hollon, a coauthor of the study. "For a lot of folks, you're going to do as well on a sugar pill or on conversations with your physicians as you will on medication. It doesn't matter what you do; it's just the fact that you're doing something." But people with very severe depression are different, he believes. "My personal view is the placebo effect gets you pretty far, but for those with very severe, more chronic conditions, it's harder to knock down and placebos are less adequate," says Hollon. Why that should be remains a mystery, admits coauthor Robert DeRubeis of the University of Pennsylvania.

Like every scientist who has stepped into the treacherous waters of antidepressant research, Hollon, DeRubeis, and their colleagues are keenly aware of the disconnect between evidence and public impression. "Prescribers, policy-makers, and consumers may not be aware that the efficacy of [antidepressants] largely has been established on the basis of studies that have included only those individuals with more severe forms of depression," something drug ads don't mention, they write. People with anything less than very severe depression "derive little specific pharmacological benefit from taking medications. Pending findings contrary to those reported here … efforts should be made to clarify to clinicians and prospective patients that … there is little evidence to suggest that [antidepressants] produce specific pharmacological benefit for the majority of patients."

Right about here, people scowl and ask how anti-depressants—especially those that raise the brain's levels of serotonin—can possibly have no direct chemical effect on the brain. Surely raising serotonin levels should right the synapses' "chemical imbalance" and lift depression. Unfortunately, the serotonin-deficit theory of depression is built on a foundation of tissue paper. How that came to be is a story in itself, but the basics are that in the 1950s scientists discovered, serendipitously, that a drug called iproniazid seemed to help some people with depression. Iproniazid increases brain levels of serotonin and norepinephrine. Ergo, low levels of those neurotransmitters must cause depression. More than 50 years on, the presumed effectiveness of antidepressants that act this way remains the chief support for the chemical-imbalance theory of depression. Absent that effectiveness, the theory hasn't a leg to stand on. Direct evidence doesn't exist. Lowering people's serotonin levels does not change their mood. And a new drug, tianeptine, which is sold in France and some other countries (but not the U.S.), turns out to be as effective as Prozac-like antidepressants that keep the synapses well supplied with serotonin. The mechanism of the new drug? It lowers brain levels of serotonin. "If depression can be equally affected by drugs that increase serotonin and by drugs that decrease it," says Kirsch, "it's hard to imagine how the benefits can be due to their chemical activity."

Perhaps antidepressants would be more effective at higher doses? Unfortunately, in 2002 Kirsch and colleagues found that high doses are hardly more effective than low ones, improving patients' depression-scale rating an average of 9.97 points vs. 9.57 points—a difference that is not statistically significant. Yet many doctors increase doses for patients who do not respond to a lower one, and many patients report improving as a result. There's a study of that, too. When researchers gave such nonresponders a higher dose, 72 percent got much better, their symptoms dropping by 50 percent or more. The catch? Only half the patients really got a higher dose. The rest, unknowingly, got the original, "ineffective" dose. It is hard to see the 72 percent who got much better on ersatz higher doses as the result of anything but the power of expectation: the doctor upped my dose, so I believe I'll get better.

Something similar may explain why some patients who aren't helped by one antidepressant do better on a second, or a third. This is often explained as "matching" patient to drug, and seemed to be confirmed by a 2006 federal study called STAR*D. Patients still suffering from depression after taking one drug were switched to a second; those who were still not better were switched to a third drug, and even a fourth. No placebos were used. At first blush, the results offered a ray of hope: 37 percent of the patients got better on the first drug, 19 percent more on their second, 6 percent more improved on their third try, and 5 percent more on their fourth. (Half of those who recovered relapsed within a year, however.)

So does STAR*D validate the idea that the key to effective treatment of depression is matching the patient to the drug? Maybe. Or maybe people improved in rounds two, three, and four because depression sometimes lifts due to changes in people's lives, or because levels of depression tend to rise and fall over time. With no one in STAR*D receiving a placebo, it is not possible to conclude with certainty that the improvements in rounds two, three, and four were because patients switched to a drug that was more effective for them. Comparable numbers might have improved if they had switched to a placebo. But STAR*D did not test for that, and so cannot rule it out.

It's tempting to look at the power of the placebo effect to alleviate depression and stick an "only" in front of it—as in, the drugs work only through the placebo effect. But there is nothing "only" about the placebo response. It can be surprisingly enduring, as a 2008 study found: "The widely held belief that the placebo response in depression is short-lived appears to be based largely on intuition and perhaps wishful thinking," scientists wrote in the Journal of Psychiatric Research. The strength of the placebo response drives drug companies nuts, since it makes showing the superiority of a new drug much harder. There is a strong placebo component in the response to drugs for pain, asthma, irritable-bowel syndrome, skin conditions such as contact dermatitis, and even Parkinson's disease. But compared with the placebo component of antidepressants, the placebo response accounts for a smaller fraction of the benefit from drugs for those disorders—on the order of 50 percent for analgesics, for instance.

Which returns us to the moral dilemma. In any year, an estimated 13.1 million to 14.2 million American adults suffer from clinical depression. At least 32 million will have the disease at some point in their life. Many of the 57 percent who receive treatment (the rest do not) are helped by medication. For that benefit to continue, they need to believe in their pills. Even Kirsch warns—in boldface type in his book, which is in stores this week—that patients on antidepressants not suddenly stop taking them. That can cause serious withdrawal symptoms, including twitches, tremors, blurred vision, and nausea—as well as depression and anxiety. Yet Kirsch is well aware that his book may have the same effect on patients as dropping the magic feather did for Dumbo: without it, the little elephant began crashing to earth. Friends and colleagues who believe Kirsch is right ask why he doesn't just shut up, since publicizing the finding that the effectiveness of antidepressants is almost entirely due to people's hopes and expectations will undermine that effectiveness.

It's all well and good to point out that psychotherapy is more effective than either pills or placebos, with dramatically lower relapse rates. But there's the little matter of reality. In the U.S., most patients with depression are treated by primary-care doctors, not psychiatrists. The latter are in short supply, especially outside cities and especially for children and adolescents. Some insurance plans discourage such care, and some psychiatrists do not accept insurance. Maybe keeping patients in the dark about the ineffectiveness of antidepressants, which for many are their only hope, is a kindness.

Or maybe not. As shown by the explicit criticism of drug companies by the authors of the recent JAMA paper, more and more scientists believe it is time to abandon the "don't ask, don't tell" policy of not digging too deeply into the reasons for the effectiveness of antidepressants. Maybe it is time to pull back the curtain and see the wizard for what he is. As for Kirsch, he insists that it is important to know that much of the benefit of antidepressants is a placebo effect. If placebos can make people better, then depression can be treated without drugs that come with serious side effects, not to mention costs. Wider recognition that antidepressants are a pharmaceutical version of the emperor's new clothes, he says, might spur patients to try other treatments. "Isn't it more important to know the truth?" he asks. Based on the impact of his work so far, it's hard to avoid answering, "Not to many people."


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Newsweek

Doctors, Depression, and DNA

Can a genetic test help patients get on the right antidepressant?

Joe Raedle / Getty Images

Click to view a gallery of drugs that changed lives for better or worse.

Psychiatrists call it the “trial and error factor”: when they set out to prescribe an antidepressant, they have no clinically proven way of knowing which one to choose. Any given antidepressant tends to help only about a third of patients; the other two-thirds end up doing the prescription shuffle, trying one drug, then another, then a third or fourth in hopes of finally hitting on a treatment that works.

In theory, pharmacogenetics—the subfield of personalized medicine that focuses on how people with different DNA variants respond to drugs—is supposed to solve this problem. The idea is to allow doctors to tailor their prescribing to their patients’ genes. But so far, despite all the research that has been done in the decade since the first draft of the Human Genome Project was released, the genetics of mental illness are still a maddeningly complex mystery.

What, then, to make of GeneSightRx, a new test that identifies variants in five genes and tells doctors which antidepressant to pick based on its results?

The test’s biggest advocate—Jim Burns, president and CEO of AssureRx, which makes it—says it is “ready for prime-time clinical use,” part of a “first wave” of long-awaited pharmacogenetic progress. The test has recently become standard of care or similar at the Mayo Clinic and Cincinnati Children’s Hospital Medical Center, the two institutions where it was developed, and it’s starting to garner enthusiasm in the press. But given how little is known about psychiatric genetics, how much trust can doctors and patients put in it? Phrased another way: if you’re planning to take an antidepressant, should you have this test first?

The scientific thinking behind GeneSightRx is actually pretty solid. Pharmacogenetics may be new to medical clinics, but it’s a mainstay of labs. At the Mayo, doctors have been laying the basic-research groundwork for how it could be used in both adults and children for three decades. Although they know fairly little about the genetics of mental illness, they know much more about genes that influence the way the body processes drugs. They’ve developed a particular expertise around a group of enzymes referred to as the “cytochrome P450 superfamily,” or CYP450 for short, which is involved in how the liver metabolizes many chemicals. If you have certain variants in the genes that make proteins in the CYP450 group, you may metabolize a drug more quickly (causing it to zoom through your system, with its effects soon wearing off) or slowly (causing it to hang around in your bloodstream, remaining effective for longer) than other people.

GeneSightRx reaps the benefits of that knowledge. Three of its five genes code for proteins involved in the CYP450 pathway. (The other two code for variants in the brain’s serotonin receptors and transporters, respectively.) “These genes are well described,” says Burns. He’s not kidding: you can read far more than you’re likely to need to know about them here, in a textbook by David Mrazek, a leader in psychiatric pharmacogenomics who—not coincidentally—is based at Mayo and was instrumental in developing GeneSightRx. Two other Mayo researchers recently published an extensive article explaining how CYP450 genotyping could be helpful in choosing antidepressants for children.

The value of GeneSightRx, however, isn’t really in the fact that it identifies CYP450 variants. In theory, your family doctor or psychiatrist could do that without GeneSightRx, by employing a firm that does “à la carte” genetic testing. The problem is that your doctor would then have to comb through the scientific literature looking for references to how your particular variants affect the metabolism of different drugs, then evaluate several antidepressants (by searching the literature some more) and choose one for you accordingly.

Few family doctors have the time to do that, if they even know it’s an option. What GeneSightRx essentially does is take all that work out, running the genetic analysis and then sorting medications into color-coded categories based on the results: green for drugs that will be safe for a patient who metabolizes them in a particular manner, yellow for those that need to be used “with caution,” and red for those to avoid.

So far, 12,000 patients at Mayo and Cincinnati Children’s have been assessed with GeneSightRx and had their meds tailored to their metabolic tendencies. “At Children’s, almost every child that comes in there [with a psychiatric diagnosis] will get a pharmacogenetic profile,” says Burns.

One of those 12,000 patients, who asked to remain anonymous, says he took the test six months ago, and it allowed him to drastically cut the dose of antidepressant he was taking—without any side effects or diminishment in its benefits. He had tried Prozac and Zoloft in the past, but those hadn’t worked. So he had switched to Effexor, which “was working fairly well,” he says. “That having been said, I thought it would not hurt to take the test, just to see the results.” The test showed the patient was metabolizing drugs slowly—meaning that a lower dose would probably be OK, because his body wasn’t burning through the drug as fast as other people’s would. The doctor cut his dose from 300mg per day to 150, and “the new dose works just fine,” he says.

Patients like him are the first targets for GeneSightRx, people who “have definitive diagnoses and have gone through multiple drug trials,” says Burns. “They’re on their third, fourth, sometimes fifth trial, or they’ve experienced adverse drug reactions and have become noncompliant. That’s who we’re targeting in the beginning.” That rationale seems to fly with insurance companies, some of which are already reimbursing for the test.

Before GeneSightRx can be expanded to all patients who might find antidepressants useful, though, there will need to be more research on its effectiveness. Specifically what’s needed is a large, well-controlled clinical trial. “With these sorts of things, the question is, what’s the state of the evidence?” says Bruce Cohen, a leading psychiatrist at Harvard-affiliated McLean Hospital who also has a Ph.D. in molecular pharmacology. “No one’s ever proven that any of these [serotinergic antidepressant] drugs are more effective than any of the others, so that’s a cautionary point right there. And no one has published and had it replicated that any set of genetic tests can be used to determine who should go on what medication. If they have gotten very strong results from 12,000 people, that needs to be published in the peer-reviewed literature and replicated before you really want to trust it.” Cohen adds that there’s a simpler way to get at whether a patient is a fast or slow metabolizer: “Ask about side effects and measure the level of drug they have in their blood.”

Still, he says, the rationale for GeneSightRx “makes some sense. Would I run off and get the test? Not on the basis of anything I know, but I’d be willing to look at their data. And there’s very low risk in doing what they’re doing. Since [choosing an antidepressant] is based on trial and error at the moment, it’s hard to imagine that adding this test could make things worse.”

The Mayo and Cincinnati doctors may soon have a response to some of Cohen’s concerns. They are running a clinical trial at three different sites in the Midwest that will ultimately involve about 500 patients. They have also begun to publish thoughtful, peer-reviewed papers considering the challenges of bringing genotyping into psychiatric clinics.

The test, too, is changing with the times. Next week, says Burns, the company hopes to add a sixth gene to the profile it can provide, and it is “on schedule to have gene 7, 8, 9, and 10 before the end of the year.” As more well-characterized genes are added to the test, it will become a more reliable guide for picking medications. For psychiatric pharmacogenetics, then, it’s still early days—but exciting ones.


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행위성 뇌질환 과 퇴행성 뇌질환을 치유하기위해서 http://biodyne.com 은 1984년 뉴욕에 설립되였다.  Mount Sinai 의과대학과 Columbia 의과대학 교수가 주축이되여 설립한 Biodyne Corporation 은 Mount Sinai 의과대학의 강성종교수가 연구회사를 재정비한후 두뇌연구소로 초점을 맟우면서 세로토닌  神經傳遞 (신경전체 Serotonin Neurotransmissions)의 연구를 핵심과제로 계속해왔다.


이 그림은 Newsweek 2010년 2월 8일 자 (한국판 뉴스위크는 2010년 2월 24일 자) 에 실린 <항우울제의 우울한 얘기> 중에서 복사했다.  

세로토닌 수체 (Serotonin Receptors) 는 현재까지 20종류가 넘는 亞型 (Subtypes) 이 발견되였고 두뇌에서 다양한 작용을 한다.  아형 5HT3 를 빼고는 모두가 Signal Transduction (信號轉導) 에 관여하는 7-跨膜G-蛋白偶聯受体 (7-Transmembrane G-Protein Coupled Receptors) 에 속한다.

지금 시판되고 있는 SSRI (Selective Serotonin Reuptake Inhibitors: 選擇性5HT重攝取抑制劑) 는 (1) 우선 제조업체가 주장하는것 처럼 선택성이 아니라는것. 예를들면 Norepinephrine 運載蛋白 (Transporter) 을 비롯 다른 神經傳遞質 (신경전체질 Neurotransmitters) 흡수도 차단한다는것, (2) 재흡수 차단 방법으로는 치료가 불가능하다는점, (3) 부작용이 심하다는것, (4) 투여후 15일에 가서 약효가 나타난다는것은 재흡수의 방법이 아니라는것, (5) 15일후에 약효가 나타난다고 주장하는것은 약이 정상적인 G-蛋白偶聯受体 (G-Protein Coupled Receptors) 에 변화를 일으킨다는것, (6) 따라서 약의 투여를 중지하면 전에 관찰하지 못했던 새로운 부작용과 심한 경우 자살로 이어진다는것 등등의 임상적 사실이 있다. 

Biodyne 연구소는 이러한 심각한 문제를 20년전 부터 알고 있었고, 이러한 접근방법은 안된다고 확신하고 새로운, 생명친화적인 방법으로 SSRI 가 아닌 G-蛋白信號轉導徑路 (G-Protein Signal Transduction Pathway) 를 활성화하여 受体를 정상화 하는것이다. Biodyne 연구소의 발표하지 않은 일차적 실험결과는 이를 증명하고 있다. 임상표현은 다르지만 이는 근본적으로 呆 (Dementia) 와도 깊이 연관되여있다. 아주 약한 MAO-A (MonoAmine Oxidase-A) 억제제의 개발도 중요한 신약개발 기술로 등장 해야한다.

지금 우울제 치료약으로 세계시장을 석권하고 있는 SSRI 의 무효론은 강성종 저, 당신의 상식 뒤집어야 건강하다, 김영사 출판사, 1997; 자궁에서 무덤까지 두뇌의 신비, 전파과학사, 2000: 당신의 두뇌 안녕하십니까? 라이프 사이언스 출판사, 2008,  http://biodyne.com; http://viaxon.com 에 잘 설명되여있다. 그 외에도 중국과학원 뇌과학연구소에서의 초빙강연, 충남대학 초청강연, 재미 과학가 연례 총회에서 SSRI 무효론을 피력한바 있다.  20년후인 지금에 와서 Newsweek 주간지가 비전문가를 위한 기사로 일반인이 알게된것은 다행한 일이다 (Newsweek 2010.02.08). 
영문판 http://www.newsweek.com/id/232781
한국어판 ttp://magazine.joins.com/newsweek/article_view.asp?aid=282419 

이와 관련해서 언급하고저 하는것은 많은 제약회사에서 개발한 이러한 SSRI 항우울증 약은 다음과 같은 강성종의 3개의 논문에서 제시된
藥效基團 (Pharmacophore) 을 응용한것이라는것이다. 그러나 이 많은 제약회사들이 생명친화성 접근방법을 고려하지 못했다는것이다.  
(1)
Kang, S. and Green, J.P.: Resonance constants and the activities of indolealkylamines on the stomch muscle. Nature 222: 794-795, 1969.
(2)
Kang, S. and Green, J.P: Correlation between activity and electronic state of hallucinogenic amphetamines. Nature 226: 645, 1970. 
(3)
Kang, S. and Green, J.P.: Steric and electronic relationships among some hallucinogenic compounds. Proc. Natl. Acad. Sci. USA. 67: 62-67, 1970.

최근 임상연구로서 SSRI 항우울증 약 효과 전혀 없다는  논문은 Child and Adolescent Psychiatry and Mental Health 3, 11, 2009. The short-term safety and efficacy of fluoxetine in depressed adolescents with alcohol and cannabis use disorders: a pilot randomized placebo-controlled trial http://www.capmh.com/content/3/1/11 에서 상세하게 읽을수 있다.
여기에서 우리가 잊어서는 않되는 사실은 安慰劑 (Placebo) 와는 달리 이 SSRI 약이 너무 독해서 임상실험 도중 탈락한다는 것이다.

여기에 몇 구절을 소개하면


Conclusion (결론):  Fluoxetine was not superior to placebo in alleviating depressive symptoms or in decreasing rates of positive drug screens in the acute treatment of adolescents with depression and a concomitant substance use disorder (SSRI 항우울제 인 푸로작 은 安慰劑 (Placebo) 보다 낳지않다. 아래 도표 참조). 

실험결과를 소개하면

 
Figure 2

Figure 3

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Hypericum Photos

11-▷ 보건 ◁ 2009. 10. 14. 12:12
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“암을 이기는 두뇌…치매도 예방 가능!”
치매, 기형아, 우울증…심각한 두뇌 질병의 원인과 예방법
 
김경탁 기자
당신의 두뇌 안녕하십니까?
 
세상의 모든 질병 중에서 가장 무섭고 끔찍한 병은 무엇일까?
 
몸의 살이 썩어들어가는 버거씨병이나 한센병, 매독, 아직까지 치료법을 찾지 못하고 있는 에이즈, 발견되면 이미 손을 쓸 수 없는 상태라는 췌장암 등… 그 양태가 끔찍한 질병이 수도 없이 있지만 의외로 ‘치매가 가장 무섭다’고 말하는 사람들이 많다.

몸은 멀쩡한데 정신과 인격이 망가지면서 그 사람의 살아온 인생 전부를 부정하도록 만드는 치매는 잊을 만 하면 한번씩 터져 나오는 연예인들의 자살 소식이나 부모자식 사이에 의해 벌어지는 존속살인 등 끔찍한 사고의 최대 원인으로 지목되는 우울증과 마찬가지로 뇌의 변화에 의해 스스로를 통제할 수 없는 질병이라는 특징을 가지고 있다.

지난해 봄부터 여름 대한민국을 떠들썩하게 만들었던 미국산 쇠고기 수입 파동이 엄청난 정서적 자극과 함께 폭발력을 가질 수 있었던 것 중 한가지는 인간광우병이 아직까지 치료가 불가능하다는 점과 함께 그 증상이 치매와 비슷하다는 점도 큰 영향을 미쳤다.

이렇게 '뇌'의 질병은 인류의 역사와 함께 결코 끝나지 않을 문제로 우리 옆에 도사리고 있는 문제이다.

세계적인 뇌과학 전문가 강성종 박사는 지난해 말 2권의 책을 냈다. 책 제목은 <한국 과학기술 백년대계를 말한다>와 <당신의 두뇌 안녕하십니까>(이상 라이프사이언스 펴냄).

<한국 과학기술 백년 대계…>의 경우 몇몇 언론매체에 소개됐지만 <당신의 두뇌…>는 아직까지 세간에 잘 알려지지 않은 상태.
 
금융경제연구소 채지윤 연구원이 강 박사의 저서 <당신의 두뇌 안녕하십니까?>에 대한 서평을 본지에 보내와 이 지면을 통해 소개한다.

 
두뇌의 적들…  

담배, 술보다 1000배 독한 ‘습관성 의약품’

경제 위기와 사회계급 스트레스 등은 질병의 주요 원인

 
글/채지윤 (금융경제연구소 연구원) 
 

환자 개인은 물론 집안 전체를 어렵게 만들고 나라의 경제까지 휘청거리게 하는 뇌질환.
 
<당신의 두뇌 안녕하십니까>는 요즘 우리의 두뇌를 좀먹게 하는 행위성 뇌질환과 퇴행성 뇌질환을 자세히 설명하고 이것에 대한 예방과 치료에 많은 신경을 기울였다.

태아에서 노년기에 이르기까지 뇌의 생성과 발달, 퇴보하는 단계에 대한 과학적인 접근을 쉬운 설명과 사례를 들어 풀어나간 이 책은 "증가추세에 있는 행위성 뇌질환과 퇴행성 뇌질환에 대한 해결책"이라는 책의 부제가 말하는 것처럼 자궁에서 무덤까지 두뇌의 생성소멸 흥망성쇠에 관해 일반 대중이 알기 쉽게 쓴 책이다.

강성종 박사는 본 서에서 치매 등 뇌질환의 원인과 예방에 대해 일반인들이 흥미를 갖기 쉽게 생활 속의 사례와 실증 분석을 통해 풀이하되, 의학적 관점에서의 깊이 있고 날카로운 진단과 새로운 시각을 함께 제시한다.

암보다 더 무서운 질병이라는 치매의 증상은 65세 이상부터 나타나기 시작하여 85세 이상 인구의 절반이 치매 환자로 집계되고 있다. 이러한 치매 질환은 갈수록 노령화되는 사회에서 최근 더욱 급속히 퍼지고 있고 점차 치매 연령층도 낮아지고 있어 심각한 사회문제로 대두되고 있다.

뿐만 아니라 대표적 정신질환이며 최근 최진실, 이은주, 정다빈 등 유명 연예인의 잇단 자살 원인이기도 한 우울증 같은 두뇌 질환은 개인과 가족, 사회에 파탄을 불러올 수 있다.

반면 두뇌를 이상적으로 이용하면, 인간은 스스로 암을 이기는 세포를 만들고, 병을 완치할 수도 있다고 한다. 실제로도 단지 병리학적 관점에서는 설명할 수 없는 불치병 완치 사례는 얼마나 많은가.
 
▲ 물체가 눈으로 들어와서 시각피질에 저장되기까지의 경로.     © 당신의 두뇌 안녕하십니까?

 
두뇌는 신체 각각의 기능을 수행하는 주체
 
본 서를 통해 저자는 인간의 두뇌가 인체의 모든 부분을 관장하고, 그 역할을 수행한다고 언급하며 ‘눈이 보고, 두뇌를 통해 판독하는 것이 아니라, 두뇌가 눈을 통해 보는 것’이라고 서술한다.

즉 두뇌는 신체 각각의 기능을 수행하는 주체라고 설명하고 있다. 그러므로 두뇌는 생각하고 판단하는 본질적인 기능을 포함해 신체의 모든 기능을 역할하고, 관장하는 가장 중요한 기관임에는 두 말할 나위가 없다.

이러한 두뇌의 생성은 태아 때부터 시작되는 부분과 태아 이후 발육하면서 발달하는 부분으로 나누어지는데, 태아 때 생성되는 두뇌는 산모의 두뇌 활용과 밀접한 관계를 갖는다고 설명한다.

예를 들어 산모가 어려운 문제를 풀거나 도전적인 일을 해결하며 두뇌를 적극적으로 활용하면, 피 속에서 두뇌를 발전시키는 생화학적 인자가 나와 그것이 모두 태아의 두뇌에게로 간다고 한다.

그러므로 저자는 산모가 태교를 위해 인사동의 화랑을 거닐며 좋은 그림을 감상하며 수준 높은 문화에 두뇌를 노출시키라고 권하고 있다.

더불어 어린아이에게도 바흐의 바로크 시대 음악과 같이 다음성 음악(polyphonic music)을 어린 시절부터 들려주거나 피아노와 같은 악기를 배우도록 하는 것도 두뇌 발달에 매우 효과적이라고 언급한다.

이는 다음성 음악의 구성과 구학의 구성은 동일하기 때문인데 이러한 음악을 들려주는 것은 결국 두뇌 생성기에 수학 능력의 지능을 올려주는 효과가 있기 때문이라고 설명하고 있다.
 
늙지 않는 ‘뇌세포’
 
최근 연구에 따르면 뇌세포는 항상 자란다고 한다. 책은 뇌세포가 태아일 때 왕성하게 분열하지만 일단 이 세상에 태어나면 뇌세포 분열이 서서히 줄어든다고 설명한다.
 
그러므로 뇌세포가 죽는 속도가 생성 속도보다 빠르면 뇌세포의 수는 점점 적어질 수밖에 없을 것이다.

그러나 엄밀히 말하면 사람은 출생 이후 새로운 뇌세포가 생성되는 속도가 느려지는 것이지, 두뇌가 단지 연령에 따라 더 빨리 노화하는 것은 아니라고 필자는 강조한다.

즉 뇌질환은 노화 현상이 아니라 두뇌를 잘못 관리한 데서 온 일종의 병이라는 것을 설명하고 다음의 실증 실험 사례를 제시한다.

“뉴욕의 마운트사이나 의과대학 실험실 실장으로 있는 북스바움 박사는 20~87세의 다양한 연령층에 속하는 사람들의 두뇌를 PET'>PET라고 하는 기계로 검사한 결과, 20세 청년과 87세 노인의 두뇌로 들어가는 혈액의 양이 아무런 차이가 없다는 사실을 발견했다.
 
PET 기계는 두뇌로 들어가는 혈액의 양이 얼마나 활발하게 그리고 골고루 들어가는지를 검출하며 두뇌의 연료인 당의 대사가 얼마나 왕성하게 움직이는지를 알아내는 기계이다.
 
이 PET로 20세의 젊은 사람 두뇌나 75세 노인의 두뇌가 모두 똑같이 왕성하다는 것을 증명한 셈이다.” 
 
두뇌는 암도 이긴다
 
하버드대 병원에서 있었던 일이다. 이 곳에서 위암을 치료받던 사람은 병이 계속해서 악화되고 암이 다른 부위로 확산되자 의료진은 더 이상의 치료가 불가능하다는 결론을 내렸다.
 
2개월 이상 살지 못할 것이라는 사형선고를 받고 그 환자는 하는 수 없이 퇴원을 했다고 한다.

이후 몇 년의 시간이 흐른 뒤 그 환자는 우연히 다른 이유로 그 병원을 다시 찾았다고 한다.
 
그런데 그녀를 본 의사들은 그녀가 기적 같은 회복을 했음을 발견하고, 하버드대 유수 의학 박사들이 정밀검사를 했지만 암이 전혀 발견되지 않고 완치되었음에 놀라지 않을 수 없었다고 한다.

이 같은 기적의 완치가 흔한 일은 아니지만, 암 선고를 받고 의사가 할 일이 없으니 집으로 돌아가서 편히 계시라는 말기 암 환자 1000명 중 1명 꼴로 이러한 기적이 일어나고 있다고 한다.

하루아침에 감쪽같이 낫는 경우도 있고, 긴 세월을 두고 완치되는 경우도 있다. 이러한 사실을 과학적으로 어떻게 설명할 수 있겠는가? 아직 정확한 원인은 밝혀지지 않았으나 충분히 가능한 일이라고 저자는 서술하고 있다.

우리 몸에는 세포인자를 비롯해서 암을 이겨낼 수 있는 요소가 많이 있는데 이것을 충분히 보충한다든가 동원하는 동량이 부족해서 일반적으로 암을 자기 능력으로 없애기는 힘들지만 두뇌가 이러한 동량을 총동원할 수 있는 생화학적 순간이 있을 수 있다면 전부 퇴치할 수도 있다는 설명이다.

때문에 암 치료는 의사의 역할도 중요하지만 암을 극복하겠다는 의지가 무엇보다도 중요하며 더불어 식이 조절과 선택, 동양의학에 의한 생물항상성 회복 등에 신경을 써야 하며 마음의 여유를 갖고 치료에 임할 것을 권하고 있다.
 
술보다 1000배 독한 담배
 
담배에는 4000종 이상의 물질이 존재하는데 그 중 70종류가 발암 유변(mutagenic) 치기(teratogenic)성 물질에 해당한다고 저자는 설명하고 있다. 그리고 그 독성은 수면제의 무려 100배에 달한다고 한다.

이런 독성의 성분을 가진 담배를 임산부가 피울 때 술의 경우와 마찬가지로 기형아 출산을 가져오는데, 술보다도 더 심한 기형아를 출산한다고 한다.

이를 태아담배증후군이라고 하는데, 이것으로 인해 성장 장애를 일으켜 나온 아이의 무게는 정상아의 40% 정도밖에 되지 않는다고 한다. 혹은 자궁 외 임신이나 조기 출산, 낙태나 사산이 경우도 빈번한데, 설령 출산을 했다고 해도 정상적인 두뇌를 유지하기 어렵다는 설명이다.

또한 저자는 산모가 흡연할 경우 출생한 아이는 일반적으로 IQ가 낮고, 자폐증이나 주의력결핍증에 걸릴 가능성도 크다고 조언한다. 게다가 임산부 시절 흡연한 아이가 성인으로 자란 후에는 조기 치매에 걸릴 확률도 높은 것으로 나타나고 있음을 밝히고 있다.
 

 “흔한 일은 아니지만, 암 선고를 받고 의사가 할 일이 없으니 집으로 돌아가서 편히 계시라는 말기 암 환자 1000명 중 1명 꼴로 기적이 일어나고 있다고 한다. 하루아침에 감쪽같이 낫는 경우도 있고, 긴 세월을 두고 완치되는 경우도 있다.”

 
경제 위기와 스트레스
 
대량실업, 감봉, 물가상승, 도산, 카드 빚, 비정규직에 이르는 경제  사회적 불안 요인은 이 시대를 살아가는 현대인들을 끊임없이 과도한 경쟁과 경제적 위기에 노출시켰다.

이는 비단 경제적인 면에서 곤란에 겪는 것으로 끝나지 않고, 이를 겪는 현대인들이 만성 스트레스라는 질병에 걸려 면역 체계가 약화되고, 혈압과 당뇨병 등 각종 성인병의 중요한 원인으로 작용한다고 저자는 설명하고 있다.

또한 낮은 계급의 사람들이 만성스트레스에 시달리고 이로 인해 많은 질병에 더 잘 걸림으로써 결과적으로 높은 계급의 사람보다 더 일찍 죽게 되는 것은 명확한 사실로, 계급사회가 빚은 폐해에 대해서도 지적하고 있다.

저자는 스트레스를 이겨내기 위해 앞으로 닥쳐올 스트레스를 예측하고 준비할 것을 조언한다. 스트레스를 푸는 것도 중요하지만, 미리 다가올 스트레스와 그 정도를 속으로 짐작하여 염두에 둠으로써 큰 쇼크를 받지 않는 것도 중요하다고 강조한다.
 
▲ 기억 시험을 하고 있는 동안 PET에 의한 두뇌의 촬영. 활발하게 움직이고 있는 부위가 흰색. 중간에서 오른쪽 후두엽 부위에 위치한 대해마와 부해마회가 활발하게 움직이고 있다.     © 당신의 두뇌 안녕하십니까?

 
치매 환자, 사랑에 빠지다
 
저자는 최근 사회적으로 가장 큰 문제가 되고 있는 노인성 치매에 대해 새로운 원인과 시각을 설명하고 있다.

미국 최초의 여성 대법관인 산드라 오코노(Sandra O'Connor)는 그녀의 남편이 17년간 치매를 앓으며 괴로워하는 모습에 종신직인 대법관 자리를 사임한다.

남편의 병상을 지키기 위해 병원으로 달려간 그녀는 남편이 같은 병실의 다른 치매환자 할머니와 사랑에 빠진 것을 발견했다. 오코노 부인은 남편이 인생의 마지막 단계에서 행복하기를 소망하며 다만 치매라는 병을 야속하게 여겼다고 한다.

이 같은 치매 환자들의 사랑 이야기를 두뇌의 대뇌피질이 소멸되어 가는 치매의 증상과 관련하여 설명해주고 있다.

치매에 걸리면 주로 대뇌피질이 먼저 소멸되어 가는데, 대뇌피질과 변연계, 이들 두뇌부분이 회로를 통하여 교류하는 부분을 통틀어 파페즈 회로라고 한다.
 
그런데 파페즈 회로는 주로 감성, 정서 또는 정감을 다루는 기능을 관여하고 있다고 한다. 즉, 치매 환자들의 애정 혹은 감정의 서툰 표현이 치매 질환의 한 증상인 것을 저자는 설명한다.
 
치매는 예방이 최우선
 
일반적으로 치매의 초기 증세는 건망증과 비슷하다고 한다.

예를 들어 방의 불을 끄고 나온 다음 불을 껐는지 안 껐는지 헷갈려 다시 확인한다거나, 열쇠를 책상 위에 놓고 다른 곳을 찾아 헤매는 정도인데, 증세가 본 궤도에 오르면 친구와의 약속을 잊어버려 약속 장소에 나가지 않기도 하고, 심하면 외출을 했다가 현재 살고 있는 집을 찾지 못하고 전에 살던 아파트로 발길을 돌리는 등 아주 단순하고 반복적인 일상도 망각하는 수준으로 진행된다고 한다.

그러나 앞서 설명한 바와 같이, 최근 연구 결과처럼 뇌세포도 항상 생성 소멸하므로, 생성을 장려하고, 소멸을 최대한 줄이면 좋은 뇌를 오래 유지할 수도 있을 것이라고 필자는 전한다.
그러므로 치매가 왜 일어나는지 원인을 먼저 알아내고 예방을 해서 치매가 생기지 않도록 하는 것이 중요한 것임에는 두말할 나위가 없을 것이다.

저서에서 강성종 박사는 뇌의 질환을 설명하면서 단순히 원인과 예방책을 제시하는 데 그치지 않는다.
 
저자는 본 저서를 통해 뇌 질환은 비단 개인의 문제가 아니라 사회 전체의 문제로 자리 잡고 있고, 동시에 사회의 문제가 뇌 질환을 야기하는 요인으로 상호 작용하는 측면을 다각적인 관점에서 독자가 함께 고민하도록 질문을 던지고 있다.

본 저서를 통해 독자가 스스로 건강한 두뇌를 지킬 수 있도록 동기부여가 되는 계기가 되길 바란다. 

금융경제연구소 채지윤 연구원 cowldbs@hanmail.net 


▲ 세계적인 뇌과학 전문가 강성종 박사.     ©법성원 제공
저자소개 : 강성종

 
세계적인 뇌과학 전문가이며, 한국인 최초로 1969년과 1970년 두 번이나 <네이처>지에 논문이 등재될 정도로 세계적 명성을 쌓은 재미 원로 과학자 강성종 박사.

그는 과학분야에서 세계적 명성 외에 정치·경제·교육 분야에 대한 탁견을 가지고 있어서 현재 금융경제연구소 고문으로도 활동하고 있다.

강성종 박사는 미국의 뉴욕시립대와 독일의 막스푸랑크 연구소 및 마인츠(Mainz)대학에서 교수를 지냈으며, 지금은 미국 바이오다인(Biodyne) 연구소에서 치매와 우울증 치료약 개발에 전념하고 있으며 한국 불교계와 인연을 맺어 해마다 한두 차례 한국을 찾고 있다

 
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