Judy Foreman

Nationally Sindicated Fitness, Health, and Medicine Columnist

A New Understanding of Depression

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At McLean Hospital in Belmont, brain researchers have hit upon what could become a totally new way to treat depression – blocking a brain chemical called dynorphin, the “evil cousin” of  endorphin, which triggers the “runner’s high.”

At the University of California, Los Angeles, psychiatrists have modified the standard EEG (or electroencephalogram) to predict which depressed patients will get better with drugs and which won’t – weeks before the patients can detect any changes in mood.

At the University of Toronto, scientists are tracing the specific components of depression – sadness, distorted thinking, disturbed sleep – to separate, but linked, regions of the brain. In the process, they’ve found one key region in the ” emotional brain,”  area 24a. If that’s overactive, depressed people improve with drug therapy; if it’s not, they won’t.

At Beth Israel Deaconess Medical Center in Boston, researchers are trying yet another approach – transcranial magnetic stimulation, which uses magnets placed on the scalp to stimulate the pre-frontal lobes of the brain, which are often sluggish in depression.

Depression, in other words, is no longer believed to be a mere deficiency of key brain chemicals – norepinephrine, dopamine and, perhaps most important, serotonin.

Today, brain researchers view this common illness, which strikes about 19 million Americans, as a malfunction of particular circuits that connect the limbic system, or “emotional brain,” with the pre-frontal cortex, or “thinking brain,” and the brain stem and hypothalamus, which control basic functions such as sleep, appetite and libido.

In truth, there never was much proof that depression was merely a serotonin deficiency. That was an inference from data showing that people who are aggressive or suicidal often have low serotonin, notes Dr. Peter Whybrow, director of the neuropsychiatric institute at UCLA. And from data showing that if researchers deprived people of tryptophan, a substance from which the body makes serotonin, they quickly got very depressed.

But now, despite the obvious efficacy of serotonin-boosting drugs such as Prozac, Zoloft and Paxil, it’s clear that when a person is depressed, there’s a lot more going wrong in specific areas of the brain than just low levels of serotonin.

The brain works by chemical and electrical signals. When an electric current passes through one cell, the cell releases a neurotransmitter, which floats to the next cell, causing it to “fire up electrically,” a process that, repeated cell after cell, activates whole circuits in the brain, notes Dr. Alvaro Pascual-Leone, director of the transcranial magnetic stimulation lab at Beth Israel. 

While most drug developers have focused on the chemical side of the equation, he notes, depression can also be treated by getting the electrical circuits back to normal. One way to do this is ECT, or electroconvulsive (“shock”) therapy, which causes a brain-wide seizure. ECT is effective, but it can also cause confusion and memory loss.

A potentially better though still experimental approach, Pascual-Leone thinks, is transcranial magnetic stimulation or TMS, which uses a magnetic field to kick-start just the pre-frontal lobes. That in turn may affect the limbic system, potentially easing depression without brain-wide seizures and memory loss.

The hallmark of depression, brain mapping shows, is too little activity in the right and left pre-frontal lobes (behind the eyes) and the right and left parietal lobes (on the side of the brain, toward the top), and too much activity in the limbic system, or emotional brain.

But the limbic system and pre-frontal lobes, which govern thinking, are actually wired together though specific neural circuits, notes Dr. Helen Mayberg, a professor of neurology and psychiatry at the University of Toronto who uses PET scans to measure blood flow and map “depression circuits” in the brain.

Indeed, the close links between the limbic system and pre-frontal lobes probably explain why depressed people not only feel bad emotionally but have trouble thinking. “For many people, yes, they are sad,” she says. “But what brings a lot of people to the doctor is the fact that they can’t think straight.”

In addition to the abnormal activity in the entire limbic system and pre-frontal lobes, scientists are finding changes in specific sub-regions when people are depressed.  The  hippocampus, for instance, a center for learning and memory, is often shrunk in depression, perhaps because it is damaged by the stress hormone, cortisol. Some scientists also think the amygdala, a fear processing center, may be involved.

And other sub-regions seem to play a role, too.  Mayberg, for instance, asks volunteers to recall a sad memory. When they start crying, she uses a PET scan to measure blood flow in the brain. The “hottest” area (the one with the biggest increase in blood flow) turns out to be a small part of the anterior cingulate called area 25, part of the limbic system. While this area gets more active,  the pre-frontal cortex, or thinking area, turns off.

In healthy people immersed in sad feelings, the brain can quickly shift back toward equilibrium. “The phone rings, the baby cries, the boss calls and you immediately disengage from the sadness and the thinking part of the brain turns back on,” she says. With depressed people, this ability to shift back to equilibrium is altered.

That may be because area 25 has direct links to area 24a, a monitoring center for emotions. In some depressed people, area 24a is virtually stuck in the “on” position, which may reflect the brain’s frantic attempt to handle upsetting feelings, Mayberg says. But that may be a good sign: Depressed people with high activity in area 24a typically get better with drug treatment, while those with low activity in 24a  don’t.

While PET scans like the ones Mayberg uses can detect changes deep in the brain, Dr. Andrew Leuchter at UCLA has found that he can predict which patients will respond to drugs with a simpler tool. Using a system called QEEG (for quantitative EEG), Leuchter studies depressed people with low activity in the pre-frontal lobes. Then he looks at what happens when they start taking Prozac, which typically takes six weeks to improve mood.

In the first few days, some people show a further decrease in pre-frontal lobe activity, particularly in the area closest to the eyes, followed about a week later, by an increase. But some people don’t show this initial decline. When Leuchter follows the patients over time, the ones who respond best to drugs are those who show the initial decline.

 “Once somebody has started on medication, we can see whether they will respond in under a week,” he says. Eventually, this should enable doctors to tell people who are likely to improve on a drug to be patient because their “brain changes are on the right track.” Those deemed unlikely to respond to a given drug can be given others drugs.

And then there are the lessons to be learned from depressed rats. Researchers who study depression in lab animals use a behavioral test called the “forced swim test.”

It works like this: Normal rats are put in a tub of water. Typically, they swim hard for 10 minutes, then give up and float until researchers take them out. The next day, they are put back in the water, whereupon they give up much faster, usually after 2 minutes. This, researchers say, illustrates the “learned helplessness” model of depression. If they are given Prozac, rats (unlike people) seem to experience an immediate benefit – they don’t stop swimming nearly as fast on the second day.

 “Every depression treatment  known to man – all drugs, electroshock therapy, TMS –  all affect the forced swim test,” says McLean neurobiologist William Carlezon.

In a recent paper in Journal of Neuroscience, Carlezon showed that there are other ways to keep rats swimming longer and, presumably, feeling good. The team focused on a protein called CREB, which activates a gene that makes dynorphin. A close cousin of endorphins and enkephalins, dynorphin is a natural painkiller. But unlike its cousins, it makes people feel “lousy, not euphoric,” says Carlezon.

Carlezon used injections into an area of the brain called the nucleus accumbens to increase or decrease  levels of CREB, and therefore dynorphin. When the rats had too much CREB, they gave up on the swim test after only one minute, suggesting that they were indeed depressed. When the researchers blocked CREB, the rats swam like champs, or more precisely, like rats on Prozac. The rats also swam a long time when given drugs that directly block dynorphin.

CREB, in other words, “is a molecular trigger for depression that acts by increasing dynorphin,” says Carlezon.  That suggests that drugs that fight depression faster than Prozac might be developed for humans, though so far no known dynorphin-blockers can enter the human brain.

Precisely how all these new pieces of the depression puzzle fit together remains a mystery. But it’s clear that not only is depression not a character flaw, it’s not even biochemically as simple as once thought. “As we  understand better the fundamental causes of depression,” says Dr. Scott Ewing, director of the depression and anxiety clinic at McLean, ” we can expect to see over the next decade antidepressants developed that will be more effective and more rapidly acting.”

Rushing Off Antidepressants Can Bring On More Distress

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At first, Zoloft seemed like “manna from heaven,” says this 53-year-old woman, a teacher who lives in Watertown.

It was the summer of 1999 and, for reasons she still doesn’t fully understand, she had slipped into a “terrible slump.” Her doctor suggested Zoloft, America’s second most popular antidepressant, after Prozac. And for a while, it was great, says the woman, who does not want her name used.

But after nearly a year on the drug, she developed a twitch in her left eyelid. It may not have been related to the Zoloft, but since she was feeling fine, she decided to stop taking the drug.

And, unlike many people who quit antidepressants, she did it the right way: very slowly – cutting the dose little by little over six weeks.

Even so, she wound up with three months of withdrawal hell, or discontinuation syndrome, the term psychiatrists prefer because withdrawal suggests that antidepressant drugs are addictive (like cocaine or heroin), which they are not.

Discontinuation syndrome is not a recurrence of the original depression, though that can happen, too. It’s a brand new set of problems, in this woman’s case, bad headaches, vertigo, and dizziness. At one point during a walk, she says, “my body felt like it was tipping to one side. I had to keep lying down. It was terrible.”

Could a drug that was no longer in her system somehow be causing weird symptoms she’d never had before?

“That was the thing that got me the most creeped out,” she says. “The drug clearly is out of your body. So what was it  that lasted for three months?”

What lasted so long for this teacher, and many others who stop taking antidepressant drugs, is what scientists now think of as a prolonged period of re-adjustment during which the chemistry of the brain settles into a kind of new, non-depressed normal.

To be sure, many of the millions of people worldwide who take antidepressants experience no withdrawal symptoms when they stop. But some studies suggest that one in every 10 have some symptoms and one in 20 suffer significant distress, says Dr. Jerrold Rosenbaum, chief of psychiatry at Massachusetts General  Hospital.

Others, among them Dr. Andrew Leuchter, director of the division of adult psychiatry at the UCLA Medical Center, believe the actual figures are much higher.

Yet even doctors who should be on the lookout for withdrawal symptoms – such as dizziness, increased nervousness, irritability, insomnia, and a dramatic increase in vivid dreams – often aren’t paying close attention.

A 1997 study in the Journal of Clinical Psychiatry showed that 70 percent of general practitioners and, surprisingly, a third of psychiatrists don’t know that significant withdrawal symptoms can occur when people stop  taking antidepressants called selective serotonin reuptake inhibitors, or SSRIs, including Prozac, Zoloft, Paxil, Luvox, Celexa, and a similar drug, Effexor. (Withdrawal syndromes can also occur with antidepressants that work differently from the SSRIs, including older drugs such  as Elavil and Tofranil)

“It’s an under-recognized problem,” says Leuchter, because when people stop taking a drug and then develop new symptoms, they can’t believe it has”anything to do with the medicine because, if they’re not taking it, how can it affect them?”

But withdrawal clearly does happen, though researchers still aren’t sure why. The basic thinking is that depression is caused by a deficiency of serotonin, a key neurotransmitter in the brain. SSRIs boost serotonin by stopping its re-absorption into brain cells, thus keeping more serotonin where it’s needed, in the synapses, or gaps, between nerve cells.

As the brain adapts to increased levels of serotonin, some neuroscientists think there is a decline in either the number or sensitivity of the brain’s molecular gateways that can put serotonin to work. Then, when SSRIs are discontinued, withdrawal symptoms may occur as the nervous system, now primed for lots of serotonin, isn’t getting enough, says Dr. Alexander Bodkin, chief of clinical psychopharmacology research at McLean Hospital in Belmont.

One thing researchers are sure of is that the severity of withdrawal symptoms from SSRIs is closely correlated with how long the drug remains in the body. The longer the drug or its active metabolic breakdown products stay in the body, the less severe the withdrawal.

“The faster-clearing the drug, the worse the withdrawal,” says Dr. Michael Craig Miller, a psychiatrist who edits the Harvard Mental Health Letter.

Prozac is least likely to cause withdrawal because its metabolic breakdown products linger in the body for as long as five weeks. In fact, precisely because of this, one strategy for people who have trouble getting off other SSRIs is to switch to Prozac and  then taper slowly off of that.

By contrast, Paxil, Luvox, and Celexa may trigger withdrawal because they are faster-clearing, lingering in the body for just four to five days. Zoloft lingers slightly longer. Effexor, a variant of standard SSRIs, has the shortest half-life of all, about 5 hours, which means it is highly likely to cause withdrawal symptoms.

Recent studies have bolstered the idea that faster-clearing drugs lead to worse withdrawal.

In 1998, Rosenbaum of MGH and his team studied 220 patients and found that those who abruptly stopped taking Paxil, and to a lesser extent, Zoloft, had significant withdrawal symptoms, while those who stopped taking Prozac did not. Another study published last year in the British Journal of Psychiatry found  essentially the same pattern.

Yet another study, sponsored by Lilly Research Laboratories (Eli Lilly makes  Prozac) and published last year in Psychoneuroendocrinology, showed that people  who suddenly stopped taking Paxil had a significant increase in heart rate and stress hormone levels, while those taking Zoloft or Prozac did not.

The bottom line is that if you want to wean yourself from antidepressants, do so slowly, by decreasing your dose by half every one to two weeks. It may take weeks or even months to discontinue completely, but that doesn’t really matter.

“There’s never a rush in getting off these medications,” says Leuchter of UCLA. “What’s the hurry? If you have been on them for six to 12 months and you’re tolerating them well, there’s no point in going too quickly.”

And if you do develop withdrawal symptoms despite tapering off slowly, try going back to the previous dose, then switching to Prozac and weaning yourself from that.

The most important lesson, says the teacher from Watertown, who is now symptom-free, is that antidepressants – despite the recent backlash in the media – significantly help millions of people. “I would never say, `Don’t go on it,’ ” she says. “I would just say be very aware that when you want to get off it, go to a doctor who knows about this.”

Is Moderate Drinking The Answer?

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Until four months ago, Paul Robert, a hard-working, 42-year-old Connecticut businessman, would get home from work and knock back six drinks a night – 45 drinks a week. Sometimes wine, sometimes beer, sometimes the hard stuff.

“It was the stress,” he says, and alcohol “absolutely” helped. He didn’t think he was a true alcoholic. His job was going great, he says, and his family life – he has a wife and two  children,  ages 7 and 10 – was, too. He’d never been arrested for driving drunk. Even his liver showed no damage from all the alcohol it processed night after night.

Deep in his heart, though, Robert knew he was drinking far too much, and he wanted to cut back. What he did not want, however, was to go the Alcoholics Anonymous route and quit completely.

Today, Robert gets counseling and a daily dose of a drug called naltrexone to reduce his craving for alcohol, allowing him to cut back to12 drinks a week. His goal is “to go back to leading a normal life, so I can go out and have a couple of drinks. I am already there.”

But Robert’s treatment at Charles River Hospital in Wellesley raises one of the most controversial questions in medicine. The idea that excessive drinkers can safely return to moderate drinking contradicts the most famous alcohol abuse program, AA, and researchers fear it gives false reassurance to alcoholics.

However, advocates of moderate drinking believe that many alcohol abusers don’t get help because they fear they’ll have to stop drinking altogether. They say moderation could significantly reduce the nation’s most pervasive substance abuse problems.

An estimated 14 million Americans either abuse alcohol – meaning they’re impaired, but not physically dependent – or they are outright alcoholics prone to uncontrolled drinking, tolerance for high doses, and withdrawal symptoms when drinking stops. All told, about 40 million Americans drink more than the recommended moderate levels – one drink a day for women, and two for men, with a drink defined as  5 ounces of wine, 1.5 ounces of spirits or 12 ounces of beer.

So, can a heavy drinker really cut back without quitting totally? Yes, but the odds of success depend on the severity of the drinking problem, and on whether you have a family history of alcohol problems. If you’re an alcohol abuser but not yet alcohol-dependent, your chances are better; if you’re truly alcohol-dependent, they’re almost zero. In fact, doctors at Charles River don’t offer the moderate drinking program to people who are physically dependent on alcohol.

The good news is that most people with alcohol problems are not dependent, according to a 1997 analysis published by the National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health.

The bad news is that the line between abuse and dependence “is in no way a clean distinction,” says University of New Mexico psychologist William R. Miller, a leading alcoholism researcher. In fact, he says, mental health experts are reconsidering whether it makes sense to maintain this distinction at all.

The problem is that people with drinking problems tend to self-diagnose, to think their problem is less severe than it really is, and to avoid seeking help. That’s one reason why the famous 12-step meetings of AA are filled with people who have tried for years and failed to control their drinking rather than quit.

The research studies on controlled drinking are both encouraging and sobering.

A series of studies by Miller’s team at the University of New Mexico shows that people without alcohol dependence can indeed return to more moderate drinking. In these studies, about two-thirds of heavy drinkers managed to reduce their drinking substantially and to maintain their success for two years. When followed for up to eight years, the success rates decline – just 15 percent had maintained moderate, problem-free drinking, 25 percent had abstained completely for at least a year, 23 percent had cut back but still had some drinking-related problems, and 37 percent were no better than when the study started. Other studies in 1980, 1984, 1988, and 1992 showed similar results.

In a pivotal study of true alcoholics – published 15 years ago in the New England Journal of Medicine but still considered noteworthy by other researchers – Dr. John Helzer, a psychiatrist at the University of Vermont Medical School, showed that only about 2 percent were able to have an occasional drink without becoming dependent again. Curiously, noted Helzer in a telephone interview, a successful return to more moderate drinking was four times more likely in women. Other studies in 1979, 1989, and 1996 also suggest that women may be more successful at cutting back than men.

Cognitive-behavioral techniques, in which people are taught to recognize and change the thinking patterns that underlie their drinking, clearly help people cut back on alcohol intake. In fact, they are among the most successful approaches for people with less severe drinking problems, according to a 1999 review of the data in Alcohol Research & Health, the journal of the Alcohol Abuse and Alcoholism Institute. Cognitive behavior also works for true alcoholics – not to help them cut down but to help them remain abstinent – according to project MATCH, a large federal study in1996.

Brief interventions, in which a doctor or nurse schedules several short appointments to teach a patient about ways to reduce intake, also reduce consumption in people who are not alcohol-dependent, according to the same1999 review. In fact, in Seattle, a 1999 study of people who wound up in the emergency room after alcohol-related accidents showed that 30 minutes of alcohol counseling from a psychologist before discharge reduced the likelihood of readmission for other alcohol-related trauma. But nationwide, many doctors and nurses have yet to incorporate this technique into their practices.

On the more discouraging side, research in 1996 by Dr. George Vaillant, director of research in psychiatry at Brigham and Women’s Hospital, tracked more than 700 college-educated and less-educated male heavy drinkers for more than 50 years. Vaillant found that men who tried to control their drinking usually relapsed while those who managed to stay sober for five years rarely did.

Yet, despite the evidence that moderate drinking leads to relapse for most alcoholics, the idea of controlled alcohol consumption is a powerful lure for alcoholics.

“Nothing is more appealing to a lot of alcoholics than the idea that if they could just figure out how to control their drinking, that would do it,” says Dr. Roger Weiss, clinical director of the alcohol and drug abuse treatment program at McLean Hospital in Belmont.

Dr. Richard K. Fuller, director of clinical and prevention research at the National Institute on Alcohol Abuse and Alcoholism, agrees. With true alcoholics, he says, its very unusual for them to return to moderate drinking. “The reason this is so sensitive, why some alcoholics become livid about this, is because they feel their own recovery was delayed for many years because they struggled, kept chasing this will of the wisp. “Most people can have a drink or two and stop. The alcohol-dependent person can’t,” Fuller added.

The limits of moderate drinking were illustrated dramatically not long ago with the tragic story of Audrey Kishline, who founded a program called Moderation Management in 1993 on the premise that heavy drinkers who are not yet alcoholics can cut back without abstaining altogether.

Last March, Kishline went on a drinking binge and killed two people in a car crash. Afterward, she reportedly called her program an example of “denial in action,” and  pleaded guilty to two counts of vehicular homicide.

Even so, Stanton Peele, a Morristown, N.J., psychologist, lawyer and former board member of Moderation Management, points out that it is ironic that Kishline’s accident happened after she joined AA and tried to abstain. It wasn’t just moderation that failed her, he says, “everything failed her.”

Advocates of  moderate drinking like Anthony Martignetti, an addiction specialist who runs the Alcarrest program at Charles River Hospital, insist that, for selected people, reduced drinking programs work.

In fact, says Martignetti (whose family, ironically enough, owns the Martignetti companies, the New England liquor distributor), it’s the fear of abstinence-only programs that keeps many people from seeking traditional treatment. So far, about 200 problem drinkers have completed Martignetti’s program, and by one year after treatment, 70 percent say they’ve reduced their drinking by 70 percent.

The bottom line? For Paul Robert, at least, things look good. He’s optimistic he can continue to drink moderately.

For others, well, let’s put it this way: If you find yourself saying”Bottoms up!” too often, see a doctor or alcohol counselor to evaluate your drinking. Trying to diagnose yourself is likely to be fraught with denial.

Then, if you and your counselor agree your problem is not severe, try a program aimed at cutting back. However, if your alcohol problem is severe, total abstinence remains the best answer.

SIDEBAR:

There are a number of medications that can help people control or cut down on their drinking, says Dr. Shelly Greenfield, medical director of the alcohol and drug abuse ambulatory treatment program at McLean Hospital in Belmont.

Antabuse (disulfiram) is a so-called “aversive” drug that causes nausea and other unpleasant symptoms if alcohol is also consumed. At high doses, the combination of  Antabuse and alcohol can be dangerous. The idea is to make the drinking experience so unpleasant that a person doesn’t drink, but this only works if people take the drug.

Naltrexone (ReVia) is an opiate-blocking drug long used to combat addiction to drugs such as heroin. In 1994, it was approved by the US Food and Drug Administration to curb craving and prevent relapse in people with alcohol problems.

Acamprosate is a drug that has shown promise in European studies to curb craving for alcohol and help maintain abstinence. It is not approved in the United States, but studies are underway.

Antidepressant drugs  that are SSRIs, or selective serotonin reuptake inhibitors, such as Prozac, have also been shown to help some people who drink too much, especially if they are also depressed.

Ambiguous Losses Leave Survivors In Limbo

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This is a love story – but one with the kind of anguished twist that millions of Americans must grapple with.

“Betsy, Betsy, Betsy, I love you,” Frederick “Pete” Peterson, now 84 and living in an assisted-living facility in Peabody, used to say, before Alzheimer’s disease slowly stole his brain.

Betsy and Pete Peterson met decades ago when Pete, then an English teacher at Phillips Academy in Andover, hired Betsy to help him run the school’s summer enrichment program.

He was tall, handsome and charming – a recreational sailor with a warm smile and a firm handshake. She was pretty, bright and vivacious. They worked together for a few years until Betsy left to become the first woman dean at Yale College. Then, after Pete’s first wife died, Betsy and Pete saw each other again – and married 22 years ago.

Now, it’s been ages since Pete called Betsy by name. “I miss that,” said Betsy, 62, who lives alone in the couple’s Boston condominium. “After a while, you realize you haven’t heard it. It’s the sort of non-event that marks the transition” from a marriage of soulmates to a strange limbo in which one spouse is alive but has lost much of his personality, while the other is essentially widowed – but without the closure, the rituals that foster healing, or the freedom to rebuild a life.

For years, psychologists had no name for the anguish of situations like that of Betsy. Now they do, thanks in part to Pauline Boss, a psychologist in the department of family social science at the University of Minnesota.

In her book, “Ambiguous Loss,” published by Harvard University Press, Boss explores the corrosive uncertainty and deep confusion faced by people who have lost, yet not quite lost, someone or something dear to them.

Sometimes, the loss occurs when a spouse has Alzheimer’s disease, or a stroke or other brain injury that leaves them alive but “not there.”

Sometimes, it’s the reverse – a loved one is physically absent but psychologically present, as happens, for instance, when children are abducted or vanish.

In fact, that’s exactly what happened 49 years ago to Betty and Kenneth Klein, now 75 and 83, whose three young sons – ages 4, 6 and 7 – simply disappeared one Saturday morning from a playground near their home in Minneapolis.

At the time, the Kleins also had one other son, age 9, and a baby on the way. After their sons’ disappearance, they went on to have three more children. But even a half-century later, their loss is as vivid – and perplexing – as ever.

When a reporter calls, for instance, Kenneth quickly summons Betty to the phone, hope and fear in his voice: “It’s about the boys.” She picks up the phone – and the story. To this day, she said, every time someone walks by or a strange car pulls into the driveway, “I always think, `Is it one of my boys?’ “

She and Kenneth have dealt with their baffling loss by praying, not blaming each other, and sticking together “very tightly,” she said.

The issue of ambiguous loss first intrigued psychologist Boss when she studied the families of pilots who had been shot down over Vietnam and were declared missing in action.

She said she found that, in contrast to more clear-cut losses, such as the death of a spouse, ambiguous losses can be even “harder to deal with because there is no closure, there’s no death certificate, there’s no public validation that this has ended.”

Carol Wogrin, a nurse, clinical psychologist and executive director of the National Center for Death Education at Mount Ida College in Newton, said that “one of the tasks of grief is really knowing that that loss has occurred. Even with a loss as clear cut as a death, she said, people often acknowledge the loss intellectually long before they really know it emotionally.

With a more ambiguous loss, emotional understanding can be harder because, Wogrin said, “a person doesn’t have all those factors that help reinforce” the reality.

It’s dangerous to get into the game of “competitive grief,” downplaying someone else’s pain because you think it’s not as bad as your own, warned Deborah Rivlin, a consultant at the Good Grief Program at Boston Medical Center, a nonprofit program that teaches grief education to children.

Still, she said, ambiguous losses can be particularly difficult, especially because, at least initially, other people may not recognize them clearly as legitimate losses. Many situations, including gradual changes like physical decline or being pushed aside at work, fall into this category.

For instance, parents who have had a stillbirth or lost a hoped-for baby to miscarriage may suffer grief that is all the more painful because the rest of the world fails to acknowledge it. This grief may even be compounded if, as used to happen routinely in hospitals, the “remains” of that pregnancy are whisked away, leaving no tiny body to cry over or bury.

But other situations may also provoke the same kind of long-term, wrenching ambiguity.

It can happen in families in which one member is an alcoholic or addicted to drugs. It can happen to children of divorce who may grieve for the death of the family, even though both parents are present in their lives. And it can happen to spouses of workaholics, who may be home in body, but whose minds are chronically at work, Boss said.

The toughest issue, she said, is the question of how not to become “frozen” in grief and how – and when – to move on.

The Kleins of Minnesota managed to move forward by realizing they had to be strong for their other children, Betty Klein said.

But does moving on, in cases where one spouse has Alzheimer’s, mean that it’s OK for the healthy spouse to form a new romantic relationship?

That issue comes up often, said Paul Raia, a psychologist at the Massachusetts chapter of the Alzheimer’s Association. “The men in my support group will date while the wife is still alive, though it’s very controversial in the group,” he said. “I have never seen a woman do that.

But other mental health specialists, including Dr. Bessel van der Kolk, professor of psychiatry at Boston University, don’t see such a clear gender breakdown on this issue.

“People need to go on with their lives,” he said, though forming a new relationship “raises enormous moral questions.” If the relationship includes sex, he said, it often generates considerable guilt. But short of that, he said, “it’s amazing how many different arrangements people make: Many people find people who meet their emotional needs.”

Betsy Peterson has tried to do just that, learning, as she puts it, “to be a widow” even though Pete is still alive.

She said she feels “very married” to Pete, still works part time as a lawyer and has “reached out a lot in the last few years,” especially to members of her church and book groups.

Even so, it’s tough. But one thought never fails to boost her spirits: “Knowing Pete has been such a gift. His friendship was such a gift. Our marriage is the best thing that’s happened in my life, so I am still ahead, even at this stage. That sense of the gift is one of the ways I get through it.”

Treatments For Manic Depression Are Improving

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Michael Penney, 53, of Holliston used to have, as he puts it, “a charmed life.” Marriage. A son. A master’s degree in marine economics and law, and good jobs, including an eight-year stint at the state office of Coastal Zone Management.

But his charmed life came to an end five years ago when he worked for an employer who humiliated him in meetings. One day, Penney erupted in a rage that stunned him as much as his colleagues. He was hustled away when he couldn’t stop sobbing.

Though the explosion seemed to come out of the blue, there had been clues. His mother and father were both mentally ill, and Penney had been very depressed in college. Even so, it took years for his psychiatrist to put the pieces together: Penney’s problem, it turns out, was manic depression, a hard-to-diagnose brain disorder that afflicts 5 to 10 million Americans.

People with manic depression have profound mood swings from paralyzing despair to agitated “highs” that can include paranoia and delusions. “Rapid cyclers” swing between these two extremes more than four times a year, and some, like Penney, swing even faster: “I can go from real bereavement to laughing like a nut in seconds,” he said.

For most of the last 50 years, there has been only one treatment for manic depression – lithium, a mood stabilizer. But lithium causes troublesome side effects, such as tremors and intestinal problems. It also may be only partially effective, and raising the dose can make side effects worse without improving symptoms.

Today, however, the outlook for people with manic depression, also known as bipolar disorder, is brightening considerably and should improve even more as a new study of manic depression – the largest psychiatric clinical research program ever undertaken – gets underway at Massachusetts General Hospital in Boston and elsewhere.

Central to the improving prospects for those with manic depression is psychiatrists’ discovery that drugs designed to treat schizophrenia – in which sufferers often endure hallucinations as well as emotional numbness – also work againstmanic depression.

That may be because of a common biochemical pathway between manic depression and schizophrenia, according to Dr. Andrew Stoll, director of the psychopharmacology research lab at McLean Hospital in Belmont. Because delusions, which are false beliefs that cannot be rationally refuted, and hallucinations, hearing or seeing things that aren’t there, often occur in both schizophrenia and mania, drugs that treat these symptoms in one disorder may help in the other as well.

In addition, these antipsychotic drugs help some people with manic depression even if they are not out of touch with reality, suggesting that the drugs directly affect mood as well as psychoses, said Dr. Nassir Ghaemi, an MGH psychiatrist.

The antipsychotic drugs that help most with manic depression include Risperdal, Seroquel and Clozaril, a medication that can also cause a potentially fatal drop in infection-fighting white blood cells. Because of this, patients taking Clozaril must get frequent blood tests.

In March, the US Food and Drug Administration increased the options for people with manic depression by approving a drug for mania called Zyprexa, already on the market for schizophrenia.

Zyprexa causes fewer side effects than the somewhat similar Clozaril and does not necessitate frequent blood tests, said Dr. Franca Centorrino, a Zyprexa researcher and director of bipolar and psychotic disorders at McLean Hospital. Its expanded approval is exciting, she said, because it’s “the first antipsychotic approved for acute mania.”

And it’s not just antipsychotic drugs that help with manic depression, but drugs that prevent convulsions, such as Depakote, Tegretol and Lamictal, as well. Two other anti-convulsants, Neurontin and Topamax, also may help stabilize mood, though the data is less clear. Designed for epilepsy, these anticonvulsant drugs may reduce the intensity of both mania and depression.

But perhaps even more important than the growing array of drug treatments – including two dozen new drugs in the pipeline – is an emerging understanding of how to combine these medications with specific talk therapies.

At MGH, the University of Pittsburgh, the University of Colorado and 17 other sites nationwide, a five-year, $20 million research project is gearing up to find the best drug and talk therapy combinations for manic depression.

Sponsored by the National Institute of Mental Health and led by Dr. Gary Sachs, director of the bipolar treatment center at Massachusetts General Hospital, the Systematic Treatment Enhancement Program for Bipolar Disorder project is now enrolling 5,000 people with bipolar disorder.

All participants in the project, known by its acronym, STEP-BD, will get one or more state-of-the-art medications for bipolar disorder; no one will be put on placebo alone.

Here’s how it will work. If a patient cruises along feeling well for months and then lapses into depression, he or she may choose whether to keep on receiving standard treatment such as lithium plus Depakote and an antidepressant such as Paxil or Wellbutrin, or to be randomized to get some combination of these and other medications, but not know which ones.

This design is aimed at getting answers to crucial questions, such as the pros and cons of using antidepressants in people with bipolar disorder. Many patients, including those misdiagnosed as depressive when they actually have manicdepression, are given antidepressants. But in some people, antidepressants can trigger mania or cause rapid cycling and a long-term worsening of disease.

In addition to choosing to be randomized for medicine, patients who relapse also will be offered a chance to be randomized to one of the talk therapies.

Talk therapies include cognitive behavioral therapy in which patients learn how to cope with their symptoms. There is also family therapy, and “interpersonal social rhythms” therapy, in which patients learn to keep normal sleep-wake cycles, a problem for people with manic depression.

It will be several years – probably 2005 – before answers from the study are in. But the mere fact that resources are being committed to the disease sends a long overdue signal that manic depression is not a matter of minor mood swings but a brain disorder that can lead to suicide.

Michael Penney knows all too well how serious his condition is. So far, his illness has kept him out of work for nearly five years, although he’s recently begun to work works 12 hours a week at Blockbuster Video in Milford. On a good day, he said, he’s grateful for the work and is reasonably content.

But on a bad day – and he still has many, despite medications and psychotherapy – he fears he will never rebuild his life. “I enjoyed all the work I used to do,” he said. “I’ll never get back to all of that.”

Go the medical route if herb doesn’t relieve depression

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So, you’re depressed. Given that the Globe’s analysis showed that, at least in lab tests, there is considerable variation among St. John’s wort brands, should you take it at all?

Buying any herbal remedy is basically a crapshoot. But the short answer is that if you try a brand of St. John’s wort and it helps within about three weeks, stick with it. Your improved mood might be due to the placebo effect – you feel better because you expect to feel better. In studies in which neither depressed patients nor doctors know who is getting a real drug and who is getting a harmless substitute, 55 to 65 percent of patients feel better on a placebo, at least for a limited time.

And in a sense, who cares? Feeling better is what counts.

If, on the other hand, you take St. John’s wort for a few weeks and still feel depressed, stop fooling around with self-medication, get to a doctor and ask about a prescription drug such as Zoloft or Prozac and/or psychotherapy.

Whatever you do, don’t take St. John’s wort and a prescription antidepressant without checking with a doctor. There are now reports of three cases of “serotonin syndrome,” a potentially fatal excess of serotonin, in people who combined St. John’s wort with a prescription antidepressant.

In a year or so, there should be more definitive answers on how well St. John’s wort works, when a $3.6 million study sponsored by the National Institute of Mental Health is completed. Led by researchers from Duke University, this study involves scientists at 12 centers nationwide, including McLean Hospital in Belmont, Mass., and will involve 336 patients who are taking St. John’s wort, Zoloft, or a placebo.

The Duke study is using a brand of St. John’s wort called Kira, made by Lichtwer Pharma AG. This is the brand that has been studied the most in Germany, where St. John’s wort is widely used.

Kira was not one of the products we tested. It contains an extract of St. John’s wort called LI 160. This extract contains hypericin and hyperforin, a compound many researchers now believe is essential to St. John’s wort efficacy.

Through its corporate ties to another German pharmaceutical company, Dr. Willmar Schwabe GmbH & Co., Lichtwer allows its LI 160 extract to be used as the basis for another St. John’s wort product, Quanterra, whose label states that it contains a variant of the extract called LI 160 WS, which means vitamin C has been added to stabilize hyperforin.

Even without the Duke study, this is already some evidence for the potential benefits of St. John’s wort for depression.

In 1996, German researchers pooled data from 23 short-term studies (using different brands of St. John’s wort) and found that it helps with mild to moderate depression; it was more effective than placebo and equivalent to standard prescription drugs.

“What is impressive is that the vast majority of studies do suggest that St. John’s wort has real antidepressant effects. If, in fact, this was nothing more than placebo, we would not expect to see such consistent results,” says Dr. Scott Ewing, director of the depression and anxiety disorders clinic and a St. John’s wort researcher at McLean. “Having said that,” he warns, “virtually all of the studies have been methodologically flawed in one respect or another.” In fact, that’s one reason why NIMH decided to sponsor the Duke study.

Anecdotally, there’s lots of support for St. John’s wort. “I’ve talked to 25 or 30 people who’ve tried it,” says Dr. Jonathan Cole, a McLean psychiatrist who is participating in the Duke study. About 15 thought it helped, he said.

“One of my informants had gotten very depressed after her pet died. She kept crying and crying. She took St. John’s wort and stopped crying. After a month, she figured she was over it and stopped taking it. She started crying again. She stopped crying again” when she resumed St. John’s wort, he said.

On the other hand, Ewing says that in his clinical experience, results “have been somewhat disappointing. Very often, people may be doing little more than giving themselves a rather expensive placebo because the substance may have lost its potency” because it’s sensitive to temperature and other factors. (St. John’s wort prices vary, but run about $1.00 a day, compared to Prozac, which can cost $5 and up a day.)

In addition to the Duke study, other research on St. John’s wort is underway or has been recently completed.

In a Massachusetts General Hospital study funded by Lichtwer, Dr. Jerry Rosenbaum, a psychiatrist, is comparing Kira to Prozac and placebo, with neither patients nor doctors knowing which patients are getting which substance.

At McLean, Ewing has just completed a study in which patients and doctors did know that all the patients were getting St. John’s wort, a brand called Alterra. “We haven’t analyzed all the data yet,” he says, but 70 to 80 percent of the 40 patients responded to the herb. He is now starting a double-blind study of 80 patients in which some will get St. John’s wort and some a placebo.

So the data aren’t all in. But at the moment, the bottom line remains: If you take St. John’s wort and it helps, great. If you try it and it doesn’t, get to a doctor for more proven remedies.

St. John’s Wort: Less Than Meets The Eye

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Globe Analysis Shows Popular Herbal Antidepressant Varies Widely In Content, Quality.

We thought it would be easy.

After all, we had just two seemingly simple questions: Does St. John’s wort, the popular herbal adtidepressant on which Americans spend $250 million a year, work – at least on rat brain cells in a test tube? And do the product labels accurately reflect what’s inside the tablets?

The path toward answers proved tortuous indeed.

We hired two companies, Paracelsian, Inc. of Ithaca, N.Y., and PhyttoChem Technologies Inc., of Chelmsford, Mass., to independently test seven St. John’s wort products we purchased and repackaged into bottles coded by number. The companies didn’t know it at the time, but we also sent each one an eight product, a placebo or inert drug, supplied to us by the Massachusetts College of Pharmacy.

We found that there was considerable chemical and biological variation among the products tested.

We’ll give you tyhe bottome line next – but read on, because the caveats are important.

On the basis of the PhytoChem analysis, only one product, Nature’s Resource, lived up to the standard claim on product lables that the products contain 0.3 percent of hypericin, a substance once thought to be the active ingredient in St. John’s wort. (Now, to be the active ingredient, but the industry continues to standardize products to 0.3 percent of hypercin.)

Four other products, Natrol, NatureMade, Herbalife, and YourLife, were lower in hypericin, containing 0.28 percent, 0.27 percent, 0.25 percent, and 0.25 percent, respectively – less than their labels claimed.

With prescription drugs, the US Food and Drug Administration allows products to contain slightly less (10 percent below) to slightly more 10 percent above) than the contents stated on the label.

With diatary supplements, the FDA insists that they contain at least 100 percent of what’s declared on the label, but because the agency does not require supplements to meet the same strigent requirements for safety and efficacy that it does for drugs, it does not specify what tests should be used to measure herbal ingredients or which labs should do them.

Although many of the products we tested fell short of their labeling numbers using the PhytoChem test, they might have passed with other testing methods in other labs.

One product, Quanterra, contained almost no hypericin, but its label makes no claim that it does.

According to the Paracelsian biological assays, only two products, Quanterra and NatureMade, passed the company’s “BioFIT” test for their ability to block the reuptake of both serotonin and dopamine, two neurotransmitters involved in depression.

(Abnormalities in the reuptake, or absorption, of serotonin and other neurotransmitters are believed to be a major cause of depression; many prescription antidepressants work by blocking the reuptake of serotonin into brain cells, thus leaving more in the synapse, or gap, between cells.)

John Cardellina, vice president for botanical sciences at the Council for Responsible Nutrition, which represents 100 manufacturers of dietary supplements, said the Globe’s chemical analysis actually “doesn’t look bad for the industry.” While only one product had as much hypericin as it listed on the label, “everybody was close to the mark. There’s not much to complain about.”

The biological assay, he felt, was more controversial. Paracelsian’s BioFIT test is “not yet an accepted practice or marker,” said Cardellina. One limitation is that, by measuring serotonin and dopamine reuptake, the test focuses on only “one of multiple mechanisms of action by which St. John’s wort works.” Another, of course, is that it is conducted in a test tube and does not involve human subjects.

Still, the fact that only two products – NatureMade and Quanterra – passed the BioFIT test is noteworthy. “Frankly, I’d expect to see more activity in that assay,” Cardellina said.

When we shared our findings with manufacturers of the products we tested, some reacted with vigorous criticism.

Although its products fared better than most, Pharmavite, which makes NatureMade and Nature’s Resource, noted there is always variability in chemical tests of herbal products. The company added it does “not believe that the data provided offers a reliable indicator of the quality of any of the brands tested.”

It also said it had “significant concerns about the manner in which the tests were conducted and the apparent reliance on limited and possibly unsubstantiated test methodology in forming any conclusions about product quality.”

On the other hand, Michael Cleary, director of product development for Natrol, Inc., welcomed our findings. “I think it’s pretty healthy” to do such a study, he said. “There was not any hint of any unfairness in any of this.”

Furthermore, he said, “To tell the truth, we expect people to pull our product off the shelf, and if they have it analyzed, to find what the label claims.”

And to many of those familiar with the largely unregulated herbal industry, including the heads of the two testing companies we hired, our findings appeared to come as no shock at all.

“It’s not surprising that few of these compounds passed,” said Timothy Maher, director of pharmaceutical services at the Massachusetts College of Pharmacy, one of our independent data reviewers.

“People are buying these products and not always getting what they pay for,” added Bernie Landes, the CEO of Paracelsian, one of the testing companies.

Even Robert Barry, the president of PhytoChem but a strong critic of our study, said that in the industry as a whole, more “rigorous study needs be done – 80 to 90 percent of what’s out there has not been subjected to tests to see whether they provide a physiological effect.”

Even if, as some in the industry point out, the bioassay used by Paracelsian measures only one of several possible mechanisms of action of St. John’s wort, and even if the chemical analysis by PhytoChem had built-in limitations, our study nevertheless shows that quality control in herbal products is a big problem.

“You have demonstrated quite nicely with this study that there is lot of variation in St. John’s wort products. I am concerned about patients self-treating a serious illness like depression with products whose contents they cannot count on,” said Dr. Serena Koenig, a physician at Brigham and Women’s Hospital in Boston who studies drug and herbal remedy interactions.

“Quality control is the number one issue in the herbal industry, no question about it,” acknowledged Mark Blumenthal, executive director of the American Botanical Council in Austin, Texas, a nonprofit research and education organization funded in part by the herbal industry.

A big part of the problem, he added, “is the lack of federal or industry policies, regulations, or requirements that stipulate a particular method of analysis for SJW [St. John’s wort] and other herbs.”

The FDA does not require that herbal remedies, which are sold as dietary supplements, be approved for safety or efficacy before they are marketed. And it allows them to stay on the market unless there is evidence of harm.

Using PhytoChem’s data, we did our own calculation and found that one product, Nature’s Resource, actually had slightly more hypericin, 0.31 percent, than its label claimed. We calculated the percent hypericin in product extracts so consumers could compare this to the 0.3 percent hypericin stated on most labels.

But PhytoChem became uneasy. In a Dec. 17 letter, PhytoChem president Barry expressed “very grave concerns regarding any conclusions that may be drawn from the very limited testing that our company was asked to peform on the Saint [sic] John’s wort products supplied by the Boston Globe.”

In interviews and in writing, Barry also expressed his strong belief that the proper methodology would have been to have both the chemical and the biological evaluations “conducted by three independent laboratories,” with at least one being a lab with no commercial interest in product testing.

Both PhytoChem and Paracelsian have a commercial interest in testing herbal products. Paracelsian plans to use its bioassay called BioFIT to provide a seal of approval for manufacturers to put on product labels. PhytoChem tests products under development for herbal and pharmaceutical companies.

Still, others in the herbal industry saw things more positively.

“I think of all the analyses done by the media, this is one of the more intriguing approaches because you have asked for chemical analysis and have looked at the emerging technology for a biological assay of the physiological activity” as well, said Cardellina of the Council for Responsible Nutrition.

“By pairing the content [chemical testing] and the activity question [biological testing], you did a good thing. . .I don’t think you can go beyond that without running a clinical trial.”

Dr. Scott Ewing, director of the depression and anxiety disorders clinic at McLean Hospital in Belmont, Mass., and a St. John’s wort researcher, wondered why the BioFIT assay looked at dopamine, a neurotransmitter that may not play as big a role in depression as serotonin, and not at epinephrine, which does play a role. (Curiously, most products we tested fared better on the dopamine test than on the serotonin assay, though it’s not clear why.)

In any case, says Ewing, the BioFIT data on dopamine “may not have any real, practical significance in terms of antidepressant effects.”

Perhaps also puzzling was the fact that there was little overlap between the biological and chemical results. Paul Blum, another of our independent data reviewers and a neuroscientist and pharmaceutical consultant in Cambridge, Mass., did a statistical analysis of the correlation of the chemical and biological findings and found “the two tests don’t correlate well with each other.”

This could be explained, however, if the chemical for which PhytoChem tested, hypericin, is not the active ingredient in St. John’s wort and some other ingredient, such as hyperforin, is.

Some of the variance in hypericin content that we found may be due to differences in raw materials and testing methods, noted Blumenthal of the American Botanical Council.

In its Dec. 9 letter to us, PhytoChem explained that it had used a spectrophotometric method called DAC 1991 to test for hypericin. Some companies test their products using an earlier test, DAC 1986. And it makes a difference.

“While not all the products passed the PhytoChem test based on the DAC 91 method, all but one would have passed by the DAC 86 standard, except for the CVS product, which comes very close,” said Blumenthal.

“Today, you can call up supply houses that sell St. John’s wort extract and you can buy two grades, one at 0.3 percent hypericin as determined by the DAC 1986 method, and the other, by the DAC 1991 method, which costs more. Therein lies part of the problem.”

Because the price difference can be as much as 30 percent, some manufacturers may buy material that meets only the easier, 1986 standard, “especially with no industry or government-mandated standards for one or the other,” said Blumenthal.

In part because of such problems, the industry is currently moving away from DAC testing toward a more precise, quantitative version of high-performance liquid chromatography testing, said Cardellina of the nutrition council.

Some of the product variance we found may also be due to other factors. St. John’s wort “is sensitive to extremes of temperature,” said Ewing, the McLean psychiatrist. It’s also sensitive to light and to humidity. That means samples “left for many months on pharmacy shelves tend to degrade and therefore lose their potency.”

Ultimately, the solution to quality control problems in the herbal industry is probably tighter regulation – of both manufacturing and labelling. If the government won’t do it, consumer pressure may force the industry to do so.

In fact, a Denver firm, Industrial Laboratories, has formed the Institute for Nutraceutical Advancement, which is funded by the herbal industry to validate methods for testing products.

Blumenthal, of the American Botanical Council, welcomes such efforts. Hopefully, he said, “one of the results of this Globe study will be to hasten the adoption by industry organizations of uniform methods of labelling standardized products – an issue that the industry has been working on for some time.”

FDA loosens reins

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The US Food and Drug Administration once had the power to force manufacturers of over-the-counter dietary supplements, including herbal remedies, to prove those products were safe, if the agency felt such a pre-market review was warranted.

That changed in 1994, when Congress passed the Dietary Supplement Health and Education Act, which gives sellers of vitamins and herbs the freedom to tout the alleged benefits of their products without much FDA intervention.

Since DSHEA, it’s been possible to put a supplement on the market and keep it there until the FDA finds clear evidence that the product is harmful. Unlike drugs regulated by the FDA, dietary supplements and herbs do not have to be proven to be safe or effective to be sold.

Before DSHEA, all health claims on supplements – as on food – had to have FDA approval before marketing. Since DSHEA, manufacturers have been able to make “structure/function” claims without prior approval. That means they haven’t been able to say a product prevents a particular disease, like depression, but they can say something vague like the product is a “mood enhancer.”

But the vagueness of struc ture/ function claims has caused considerable confusion among consumers. In response to that, last week, the FDA issued a new ruling on disease claims, which takes effect in 29 days.

It states that a number of common conditions such as aging and pregnancy are normal life stages, not diseases, and therefore manufacturers can make structure/function claims for products aimed at them, says Peggy Dotzel, acting associate commissioner for policy at the FDA.

But some consumer advocates say the ruling is a blow to consumer protection. The change is a “huge weakening” of the previous FDA proposal, says Dr. Sidney M. Wolfe, director of Public Health Citizen Research Group in Washington, D.C. It is “a snake-oil exemption” and a “complete cave-in to the industry.”

On the other hand, industry representatives were delighted.

“The FDA has backed down from its previous, ill-considered proposal to redefine the word `disease’ by broadening it. . .to include nonpathological states that are a normal function of aging or the body,” said Mark Blumenthal, executive director of the American Botanical Council in Austin, Texas, a nonprofit research and education organization funded in part by the herbal industry.

Under the FDA’s original proposal, “menopause would be considered a disease. Even balding and graying of a beard would have been considered a disease,” he said.

In essence, he added, the final rule now “allows herbal products to continue making certain kinds of claims that might not have been able to be made had that definition of disease gone into final status.”

With manufacturing of herbal products, DSHEA requires only that manufacturers produce them in accordance with “good manufacturing practices” of the food industry. But there is a wide range of standards within the food regulations, which are often less stringent than those in the pharmaceutical industry.

The FDA is now writing more stringent manufacturing regulations for supplements and has sought comments from supplement makers and the public.

While the United States continues to struggle with ways to regulate the herbal industry, other countries have long had a better grip on things.

In Germany, herbal products are regulated largely as pharmaceuticals – both as prescription and over-the-counter drugs, notes John Cardellina of the Council for Responsible Nutrition, a Washington-based group representing the supplement industry. But, he adds, the German “approval process for drugs is not as stringent as the FDA approval process.”

Trendy pill should be taken with a grain of salt

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She’s a young woman from the South Shore, finally able both to work and to study for an advanced degree.

But for years, she’s been plagued by severe depression that stems, she says, from physical abuse she suffered as a child, and from sexual abuse when she was 17.

She tried Prozac and, by her count, 30 other antidepressant drugs. Nothing worked. Psychotherapy helped some, and still does, but not enough.

She’s been suicidal. She still has nightmares and flashbacks. Until a few months ago, the woman, who did not want her age, occupation or town published, felt she had no options left.

Then she tried SAM-e, the European prescription antidepressant that in recent months has been growing here in popularity, despite its $10-a-day price tag. The preparation is now available as an over-the-counter remedy in US health food stores.

“I haven’t felt as depressed,” says the woman, who has been taking 800 milligrams a day of SAM-e for several months. “It sounds corny, but I just have experienced more joy lately.”

Neither an herb nor a vitamin, SAM-e (pronounced “Sammy”) is a synthetic form of a chemical made in the body from methionine, an amino acid, and an energy molecule called ATP. It helps with dozens of metabolic functions from preservation of cell membranes to DNA replication.

In fact, it’s been studied and used for years in Italy as an antidepressant. In the US, the potential market for it is huge – 18 million Americans suffer from depression.

Because it is sold as a dietary supplement, SAM-e did not have to pass safety or efficacy review by the US Food and Drug Administration. But because it contains a “new ingredient” (S-adenosylmethionine), manufacturers must inform the FDA of their intent to sell it. By law, if the FDA does not object within a defined time period – and it has not with SAM-e – the new ingredient may be sold.

It’s not at all clear how SAM-e might combat depression. It does not work as Prozac-type drugs do, by blocking re-uptake of a brain chemical called serotonin. It may act by improving the elasticity of cell membranes or by stabilizing receptors on cell membranes, but this is unproved.

Still, there’s evidence that some depressed people may be low in SAM-e, and that taking SAM-e supplements may help. In a 1990 study of 30 depressed people, one third had low levels of SAM-e in the cerebrospinal fluid, says Teodoro Bottiglieri, the leader of that research and director of the neuropharmacology lab at Baylor Institute of Metabolic Disease in Dallas.

Several animal studies and one placebo-controlled human study suggest that SAM-e can boost serotonin levels. Other evidence suggests SAM-e may also raise levels of dopamine and norepinephrine, two other brain chemicals often involved in depression.

But the best – albeit flawed – evidence for SAM-e comes from a 1994 Italian analysis of pooled data from 13 clinical trials. Taken together, six studies showed SAM-e was better than a placebo at reducing depression. The other studies suggested SAM-e was equal in efficacy to older, tricyclic antidepressants, which have been shown to be about as effective as newer antidpressants such as Prozac.

Yet even psychiatrists who recommend SAM-e are cautious.

“It is not a good first-line drug. It’s something to consider as a possible alternative when other things have failed,” says Dr. Maurizio Fava, a psychiatrist at Massachusetts General Hospital. So far, he says, most studies are too small to carry much statistical weight and use poorly defined groups of depressed patients.

Dr. Scott Ewing, director of the depression and anxiety disorders clinic at McLean Hospital in Belmont, agrees.

“Every year or so, there’s a new antidepressant du jour. Right now SAM-e is it. A couple of years ago, it was St. John’s wort,” he says. But SAM-e research “is not of the highest quality.”

The studies have typically followed patients for four weeks or less. Since many depressed patients feel better in a few weeks even taking a placebo, these results may be meaningless. A study that followed people for 8 to 12 weeks would be more convincing, say psychiatrists, because the placebo effect often wears off by this point.

Still, Ewing supports the use of SAM-e in his patients who can’t tolerate side-effects of other antidepressants, partly because it appears to have few side effects and to be safe.

It may also take effect sooner than standard antidepressants and may, if taken with them, boost their effectiveness, he says. But this is unproven, warns Ewing, and there are other ways to boost the potency of antidepressants for which there is good evidence.

Dr. Jerry Rosenbaum, associate chief of psychiatry for clinical research at MGH, keeps SAM-e for “situations where I’m striking out with the patient on side effects.” But even when it helps, he says, the benefits don’t always last.

On the other hand, Dr. Richard Brown, associate professor of clinical psychiatry at Columbia University in New York, is an unabashed SAM-e proponent. In his book [see sidebar], Brown calls SAM-e a “breakthrough supplement” and claims that it “begins to relieve depression in seven days.” In a telephone interview, he adds that he’s now treated hundreds of people with SAM-e.

In order for the body to make SAM-e, a person must have adequate levels of folate (which in turn is made from folic acid, a vitamin) and vitamin B-12. (In fact, adding folate to standard antidepressants may increase their benefit.)

Once it’s made, enzymes interact with SAM-e, causing it to give up a part of its chemical structure called a methyl group. In particular, SAM-e donates methyl groups to cell membranes, to big proteins inside cells and to small ones outside cells like the neurotransmitters serotonin, norepinephrine, and dopamine.

For instance, when lipids in cell membranes are well supplied with methyl groups, the membranes remain elastic, says Bottiglieri. This allows receptors in the membrane, including those for some neurotransmitters involved in depression, to move around as they need to, carrying chemical signals.

Still, nobody really understands how SAM-e might work in depression, so if you try it, do so under a doctor’s supervision, assuming you can find a doctor open-minded enough to read what research is available.

Because SAM-e is poorly understood, don’t try it if you have manic-depression, because some antidepressants may make mania worse. It’s also important to take tablets that are enterically coated so they dissolve in the intestines, not the stomach, where they can be absorbed, and that are foil-wrapped so they do not absorb moisture.

Also make sure that your SAM-e product contains 1,4-butanedislfonate, a stabilizer. If not stabilized, SAM-e products can degrade and become useless. In fact, that’s what happened a decade ago when MGH researchers Fava and Rosenbaum did a SAM-e study with 40 patients.

The study was “a bust,” they say, because the tablets they had ordered from Italy sat unrefrigerated over a hot weekend at Logan airport. The pills became discolored, suggesting oxidation, and perhaps because of this, patients who took them did no better than those on a placebo.

There’s also a theoretical possibility that SAM-e might raise levels of homocysteine, an amino acid that can raise the risk of heart disease.

And there’s one final caveat. Several US researchers now at the forefront of SAM-e research have in the past or are now planning to do research supported by Nature Made, which sells a SAM-e product.

This does not necessarily mean the researchers are unethical or their findings won’t be credible. But it’s something to chew on.

Here’s to your health: the benefits of drinking outweigh the risks, but only within limits

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On Thursday, the French will go nuts.

We know this because they go nuts every year on the third Thursday of November, the day the latest crop of just-off-the-vine wines hit the market.

Wine-lovers will swarm to those cute little bistros, swell with Gallic pride, swill a glass of this fairly flimsy red stuff, and proclaim, “Le Beaujolais Nouveau est arrive!”

(This proves either that the French really do have a better grip on things than the rest of us, as I suspect, or that they, too, can be suckered into a clever marketing ploy. Or both.)

But it’s not just the French who love wine. In recent years, American wine sales have been booming, too. Nobody knows why, but it may be that Americans have come to believe that wine is actually good for them.

And so it is. In the last quarter century, more than 50 studies from around the world have shown that people who drink moderately have up to a 40 percent lower risk of heart disease than those who don’t drink. Because heart disease is such a huge factor in overall mortality in the US, this translates statistically into a lower death rate in any given year for moderate drinkers.

But the whole truth — in vino, veritas — is a bit more complicated, so before you pop that cork, some caveats.

By government estimates, 14 million Americans have an alcohol disorder, which is defined as abuse and dependence (or uncontrolled drinking), tolerance for high doses, and withdrawal symptoms when drinking stops.

In excessive amounts, alcohol raises the risk of heart disease, hypertension, stroke, some cancers, violence, and suicide. It’s also bad for pregnant women because it can cause defects in the developing fetus. It shouldn’t be mixed with certain medications (check the labels). And it clearly doesn’t mix with driving.

For the record, alcohol consumption can also be tough to study because people sometimes lie about how much they drink. It’s especially tough to sort out the relative merits of wine, beer, and liquor because people typically drink different types of alcohol on different occasions.

Beyond that, researchers don’t always agree on what counts as “moderate drinking,” though it’s usually one drink a day for women and two for men, with a drink being 5 ounces of wine, 1.5 ounces of spirits or 12 ounces of beer.

That said, compared to most medical research, the data on alcohol and health are remarkably clear, consistent, and compelling, though things get murky on the finer points, like whether wine, especially red wine, is better than other alcohol.

The first hints that alcohol might carry health benefits came 25 years ago — as a surprise.

With a colleague, Dr. Arthur Klatsky, now a senior consultant in cardiology at Kaiser Permanente Medical Center in Oakland, Calif., was studying factors that predicted heart attacks.

In a 1974 study, Klatsky says, there was no hypothesis about alcohol, but he asked about drinking anyway and found that abstainers were actually at higher risk of heart attack than those who drank moderately. No one knew why.

Now scientists think they do. Alcohol, whether from wine, beer or spirits, raises HDL, or “good” cholesterol, and lowers levels of a blood-clotting protein called fibrinogen and reduces the activity of platelets, which also help form clots. (A recent Stanford University study showed alcohol may also help reduce the damage done to tissue during a heart attack — at least in rats.)

The study that clinched the link between moderate drinking and overall survival came in 1997. Researchers led by Dr. Michael J. Thun, who heads epidemiological research for the American Cancer Society in Atlanta, studied 490,000 people and found that moderate drinkers had a 20 percent lower risk of death in any given year than abstainers.

This holds true for women as well as men, Thun says, though he’s quick to warn that the risk-benefit ratio is trickier for women. That’s because the risk of dying from (not just getting) breast cancer is 30 percent higher among women who have at least one drink a day.

“For breast cancer, not drinking at all would be optimal,” he says. Yet because heart disease kills six times as many women as breast cancer, the benefits of moderate drinking still outweigh the risks for many women.

Here’s another way of looking at it. A huge, 1998 Harvard study of pooled data on 322,000 women found that the risk of getting breast cancer goes up linearly with the amount (though not the type) of alcohol consumed; one drink a day raises risk about 10 percent. Put another way, a woman who lives to age 85 has a 12.5 percent chance of getting breast cancer; adding a drink a day raises this to 13.6 percent. (On the other hand, just to confuse matters, a smaller study published in January and based on data from the ongoing Framingham Heart Study showed that women who drink one alcoholic beverage a day have no increased risk of breast cancer.)

If there is an increased risk, it’s modest and probably due to the fact that alcohol raises blood levels of estrogen, at least transiently, and estrogen can drive some breast cancers.

But this increased breast cancer risk from drinking is less than that from estrogen supplements, which raise risk about 40 percent in menopausal women who take them for five years or more. Even adding together the increased risk from a drink a day to the increased risk from hormone therapy, that’s still only a 50 percent increase in the risk of breast cancer, fairly modest by statistical standards. This may be a crucial difference for women with a strong family history of breast cancer, but for others, the benefits of alcohol may still outweigh the risks.

And what of the notion that red wine has even more health benefits than lowlier forms of booze? That gets tricky.

The theory is that many phenolic compounds in the seeds of grapes and a particular one called resveratrol from grape skins act as potent anti-oxidants, or disease-fighting chemicals. Grape seeds and skins are used in making red wine (and purple grape juice), but not white wine, notes wine chemist Andrew L. Waterhouse of the University of California, Davis.

In a study published in September, Waterhouse showed that a phenolic compound called a catechin shows up in the blood after people drink red wine. Other research has shown that red wine, but not white, causes changes in the blood that make it harder for LDL, or “bad” cholesterol, to be oxidized and thereby perhaps to help form artery-clogging plaques.

Researchers from the University of Wisconsin also reported recently that in 15 people who drank purple grape juice every day, blood vessels were more elastic and LDL cholesterol was oxidized more slowly.

But does this translate into real differences in disease?

Some researchers think so. In 1995, Danish epidemiologist Morten Gronbaek reported in the Copenhagen City Heart Study of 13,000 men and women that the risk of dying was reduced by 50 percent in people who had three to five glasses of wine a day. He did not find the same benefit for beer or spirits.

But he also found in a 1999 study that people who drank wine were more likely than those who drank beer or spirits to eat a healthful diet, with lots of fruits, veggies, fish, and olive oil.

Klatsky, the Kaiser Permanente cardiologist, has also looked for any special effect of wine and has concluded that if there is a benefit to wine over other forms of alcohol, it’s probably not the wine but the health habits of the people who drink it.

Eric Rimm, a nutritional epidemiologist at the Harvard School of Public Health, puts it this way. About one third of the 50 worldwide studies on alcohol and health look at wine, beer, and spirits separately. Taken together, he says, there’s no compelling evidence that red wine has more health benefits than other types of alcohol.

To which the only decent answer is a raised glass, a Gallic shrug, and a hearty, “C’est la vie!”

SIDEBAR: LABELS CAN’T TELL THE STORY

In February, the government took a long-awaited step toward legitimizing wine consumption when, at the urging of wine manufacturers, the Bureau of Alcohol, Tobacco and Firearms approved a voluntary label for wine bottles that refers consumers who want “to learn the health effects of wine consumption” to the agriculture department’s Web site.

But last month, the agency bowed to political pressure from Sen. Strom Thurmond (R-S.C.), and announced it was re-opening the issue for public comment. Last week, John De Luca, president and CEO of the California-based Wine Institute, an industry-supported group, said, “Far from fearing this, we welcome it. It’s a terrific new forum to share the scientific findings on the subject.”

The new label approved in February did not replace the required label carrying the US Surgeon General’s warning that pregnant women should not drink alcohol because of the risk of birth defects and that drinking alcohol impairs the ability to drive a car or operate machinery and may cause health problems.

It didn’t make outright health claims, either, but did refer readers to the US Department of Agriculture’s statement, which says that in moderation, alcohol is associated with a lower risk of coronary heart disease. The USDA defines moderate drinking as no more than one drink a day for women and no more than two for men.

To read the full USDA statement on the Web, go to http://www.usda.gov/fcs/cnpp.htm

For more information on the health effects of wine and other forms of alcohol, check out the Web site of The Wine Institute at http://www.wineinstitute.org. It’s an industry site, but has done a decent job of pulling together some scientific studies.