Modern anti-depressants, for which Americans spent more than $5.6 billion last year, have been a huge boon, partly because they have few disastrous side effects, even in overdose.

With older, “tricyclic” anti-depressants like Elavil, for instance, “a 10-day supply could kill you,” says Dr. Michael Jenike, associate chief of psychiatry at Massachusetts General Hospital. The newer drugs, called SSRIs, or selective serotonin reuptake inhibitors, are rarely fatal.

The leading SSRIs — Prozac, Zoloft and Paxil — also sidestep a hazard of older anti-depressants: MAO inhibitors like Nardil and Parnate can cause a fatal rise in blood pressure when taken with red wine, aged cheese and other foods.

But for all their magic against both depression and anxiety, the SSRIs do have drawbacks. Like the older drugs, they can take weeks to kick in. They can also cause sexual dysfunction (lack of orgasm) and, initially, agitation. (A fourth SSRI, Luvox, which combats depression but is approved for obessessive compulsive disorder, may be somewhat less likely to cause sexual dysfunction.)

Worse yet, the SSRIs don’t work for nearly a third of the people who try them.

This is frustrating for the 18 million Americans who are depressed and 23 million more who are anxious, but it’s strong motivation for drug companies racing to find better drugs.

And they are, including new classes of anti-depressants designed to act through entirely different pathways in the brain — drugs that block a brain chemical called substance P and others that block CRH, corticotropin releasing hormone.

Spurring this effort is an explosion of basic knowledge about the brain, some of which will be presented this week in Washington by the Dana Alliance for Brain Initiatives, a nonprofit organization involving more than 185 neuroscientists.

“For four decades, we have been increasingly perfecting anti-depressant drugs,” says Dr. Steven Hyman, director of the National Institute of Mental Health. “Now, for the first time. . .we are beginning to see the possibility of real alternatives.”

Much of the excitement comes from the growing recognition that an almond-sized brain structure called the amygdala plays a central role in the processing of fear and almost certainly in depression and chronic anxiety as well.

The amygdala is rich in receptors for substance P, a brain chemical originally thought to transmit pain signals but now believed to be more important for depression and anxiety. The amygdala is also rich in receptors for CRH, the stress hormone.

At the same time that drug makers are scrambling to find drugs to block CRH and substance P, they are scurrying to improve the current SSRIs, which combat depression and anxiety by increasing levels of a brain chemical called serotonin in the synapse, or space, between nerve cells.

Scientists have never proven that depression is caused by a deficiency of serotonin, but they have found low serotonin levels in studies of people who are aggressive or suicidal, says Dr. Peter Whybrow, director of the neuropsychiatric institute at UCLA. Increasing serotonin, he adds, is a “fulcrum where one can intervene,” but there may be even deeper root causes of depression yet to be found.

In recent years, scientists have discovered that there are at least 15 subtypes of serotonin receptors on brain cells, as well as subtypes for two other neurotranmitters, norepinephrine and dopamine, that are also involved in depression.

This is crucial information: It means scientists should be able to tailor a drug so it acts on some receptors and not others, keeping anti-depressant activity high while minimizing side effects like time lag to efficacy and sexual dysfunction.

Here’s how it works: An electrical signal travels down one brain cell, telling it to release serotonin into the synapse. The serotonin lands on “post-synaptic” receptors across the synapse in the next cell, triggering new signals in that cell.

Serotonin then floats back toward the first, or presynaptic, cell, which sucks some of it in through a “re-uptake pump” to be recycled for further use. It is this re-uptake system that the current SSRI drugs block.

But brain cells also have “autoreceptors” that interact with serotonin in another way — by telling the cell when there’s enough serotonin in the synapse that no more needs to be made, in essence, a negative feedback loop.

Scientists now think that one reason it takes so long for SSRIs to kick in is that it takes weeks for the cell to learn to “ignore” this feedback and start making more serotonin, says Dr. Scott Ewing, director of the depression and anxiety service at McLean Hospital in Belmont. By tinkering with drugs aimed at these autoreceptors, he says, it should be possible to make drugs that work faster, though none are available yet.

Similarly, better knowledge of receptors has led to drugs like Serzone and Remeron, which have fewer sexual side effects because they block certain post-synaptic serotonin receptors.

A new SSRI, Celexa, approved last fall, avoids still other pitfalls than standard SSRIs by triggering fewer interactions with other drugs.

Researchers are also discovering other ways to help people who don’t respond to standard drugs. For instance, some data suggest that taking a blood pressure drug called pindolol with an SSRI makes the SSRI act sooner by acting on the presynaptic autoreceptors to stop the negative feedback loop.

SSRIs can also be made more effective by taking them with other drugs like lithium (normally used for manic-depression), a synthetic thyroid hormone called T3, an anti-anxiety medication called Buspar or tricyclic anti-depressants, says Ewing.

Sometimes, combining two “atypical” anti-depressants like Wellbutrin, Effexor, Serzone or Remeron, also helps people who have not responded to other drugs.

The bottom line is that “if you’re doing well on your current anti-depressant and can stand the side effects, stay on it,” says Ewing. After all, anything you switch to may bring new side effects. “It’s a mistake to go off a drug you’re responding to.”

But if you’re not responding well, don’t give up. Psychotherapy, the talking treatment, can be very effective, even without medications, for many people. The herbal antidepressant St. John’s Wort seems to help many people, too.

And if you do want to switch to a different prescription anti-depressant, talk to you doctor. If he or she can’t provide an answer, see a psychiatrist or psychopharmacologist. Remember: Depression and anxiety are highly treatable problems.

SIDEBAR

Some of the new anti-depressants in the pipeline

Substance P blockers: In terms of published data, Merck Research Laboratories is the leader. Six months ago, it reported in Science that its drug MK-869, worked as well as Paxil in depressed people. Since then, the company says it has finished an unpublished study with less clear results and is now pursuing an unnamed substance P blocker it feels is more potent.

A number of other companies, including Pfizer Inc. and Eli Lilly & Co. are also working on substance P blockers.

Corticotropin releasing hormone (CRH) blockers: Published data are scanty, but informal reports “look promising,” says Dr. Steven Hyman, director of the National Institute of Mental Health. A 1998 study in Munich showed that mice missing a receptor for CRH exhibited reduced anxiety and stress, suggesting that CRH blockers might be effective in humans.

Improvements to SSRIs, or selective serotonin reuptake inhibitors. Many companies are working on this. Lilly and Sepracor are working on R-fluoxetine, a Prozac variant with fewer side effects. Celexa, already on the market by Forest Laboratories, Inc., causes less agitation than standard SSRIs.

Other serotonin-based drugs. Solvay Pharmaceuticals is working on flesinoxan, which boosts serotonin by increasing the activity of a particular receptor called 5-HT1A.

Norepinephrine reuptake inhibitors. This is a new class of drugs that would boost a different neurotransmitter, norepinephrine. So far, Pharmacia & Upjohn’s drug, reboxetine, appears closest to getting approval for marketing.

RIMAS, or reversible inhibitors of monoamine oxidase. The idea is to tinker with MAO inhibitors so a patient doesn’t have to follow a special diet. A drug called moclobemide is already on the market in Great Britain, Canada and Europe to do this. It’s not clear whether any company will bring it to market in the US.

Glutamate drugs. Some scientists think this important neurotransmitter may play a role in depression, as it does in Alzheimer’s disease and schizophrenia. Lilly is exploring this.

Herbal antidepressants. The leader is St. John’s Wort, already shown to be effective in European studies. McLean Hospital is studying a sustained release form of the drug. There’s another study at 12 centers nationwide. If you want to participate, call 617 855 2862 for the first study, or 919 668 8991 for the second. (On the web, you can find out more about the second study at http://hypericum.rti.org.)

Fish oils that are already believed to reduce the risk of heart disease may help combat a number of serious psychiatric illnesses as well, researchers said yesterday.

At an international conference sponsored by the National Institutes of Health, scientists said that though the data are preliminary, a growing body of evidence suggests that higher consumption of essential fatty acids in the oils, notably one called omega-3, appears linked to a lower risk of depression and better treatment of manic-depression and schizophrenia.

Essential fatty acids must be consumed in the diet or as supplements because the body cannot make them. A major dietary source of omega-3 is fatty fish such as mackerel, Atlantic salmon, bluefish, halibut, herring, and sockeye salmon.

The researchers did not make specific recommendations for consuming fish or omega-3 supplements. But previous research suggested that eating fish two to three times a week is healthful, says Larry Lindner, executive editor of the Tufts University Health & Nutrition Letter.

People seeking to increase their consumption of omega-3 fatty acids also can eat green leafy vegetables, nuts, flaxseed, and canola oils, which contain fatty acids that the body can make into two chemicals, called EPA and DHA, that are thought to produce the health benefits. The researchers said they had no definitive answers on whether DHA, which is found in breast milk, should be added to infant formula in America, as it is in Europe and Asia.

Consuming high quantities of omega-3 supplements, however, can suppress immune function, conceivably leaving people more vulnerable to infection. On the other hand, Lindner said, omega-3 supplements seem to help people with arthritis, an auto-immune disorder. A 3,000-milligram daily dose has been shown to reduce arthritis symptoms caused by immune system damage to joint tissue. Omega-3 also can reduce the ability of the blood to clot, which means it could be hazardous in a person with a bleeding disorder.

The research includes data suggesting that countries where large quantities of fish are eaten have lower rates of depression than countries where fish is not a major part of the diet, said Dr. Joseph R. Hibbeln, chief of the outpatient clinic at the National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health.

Major depression is 60 times more prevalent in some countries than others, Hibbeln said. Fish consumption appears to be an “important protective factor.”

Lindner called the link between fish oils and reduced incidence of depression “provocative,” but said it was “too early to make a recommendation that people suffering from a mood disorder should eat more fish or start taking omega-3 supplements.”

Hibbeln’s team found that higher blood levels of two omega-3 fatty acids (EPA and DHA) in both normal people and alcoholics correlated with higher levels of an important brain chemical, serotonin. This suggests, he said, that consuming omega-3 fatty acids may influence production of serotonin. Many scientists believe that low levels of serotonin are linked to depressive, suicidal, or violent behavior.

In one study of 18 suicidal patients, higher blood levels of EPA were linked to lower scores on tests that predict suicide, Hibbeln noted. The emerging data, taken as a whole, suggest that EPA and DHA may reduce depressive and suicidal behavior.

Dr. Andrew L. Stoll, director of psychopharmacology at Brigham and Women’s Hospital in Boston, reported what he called “very exciting” results from a study of about 50 patients with manic-depression, or bipolar disorder, which affects an estimated 2 million Americans.

About half the patients were given 10 grams a day of omega-3 (equal to several servings of fish) in a special formulation and the other half received a placebo made of olive oil. All patients continued to receive their usual medications as well.

The study was planned to last nine months, said Stoll, but after four months the rate of relapse in the omega-3 group was dramatically lower, prompting researchers to stop the study early. Although it is not totally clear how omega-3 works, Stoll said, it appears to act like lithium and valproate, two manic-depression medications that block transmission of neurochemical signals inside brain cells.

Omega-3 fatty acids also appear to help reduce symptoms of schizophrenia in people taking standard medications, said Dr. Malcolm Peet, head of psychiatry at the University of Sheffield in the United Kingdom. Schizophrenia, which affects 1 percent of the population, produces delusions, hallucinations, apathy, and withdrawal.

Peet has found that levels of fatty acids are lower in people with schizophrenia. In three small studies, he said, giving omega-3 supplements to schizophrenic patients appears to lessen the severity of symptoms.

Alan Schlingenbaum, a 43-year-old computer consultant in Wellesley, was a regular guy. Which is to say, he got his work done and acted “the way a male acts on the world,” he says.

What he “wasn’t so good at” was intimacy — with his wife, his friends and himself.

His wife — now his ex-wife — dragged him into therapy with Terrence Real, a Watertown social worker and author of “I Don’t Want to Talk About It,” the best-selling book about men and depression.

Sure enough, after a few sessions, Real told him he was depressed.

“What are you talking about? You’re crazy!” Schlingenbaum retorted. Then he read Real’s book and became a convert.

Through therapy and a men’s group, he says he’s turned his covert depression into overt depression and is the better for it: “Just what I’ve learned so far is paying off for me in the kinds of relationships I have.”

Real, who is co-director, with psychologist Carol Gilligan, of the Harvard University Gender Research Project and a senior faculty member of the Family Institute of Cambridge, contends that depression is a “hidden epidemic” among men. If covert depression is taken into account, he argues, men are just as depressed as women, despite reams of statistics to the contrary.

“There’s a cultural collusion in covering this up,” he says, because men are brought up to disavow their feelings.

The result of all this unacknowledged depression, Real says, is an “unholy triad” of behavior — self-medication (by drinking, gambling, drugging, compulsive spending, sex, TV or work), isolation and lashing out (irritability, abuse and murder).

Not a pretty picture, but could all those “bad” guys be depressed?

“That’s ridiculous. . . It’s like saying you really have something but it looks like something else. If it looks like something else, it is something else,” says Dr. Myrna Weissman, a Columbia University psychiatrist who studies the incidence of psychological disorders.

Slapping a diagnosis on men who act out may even do harm because it “gives someone the sick role when maybe they’re just not very nice,” says Weissman, whose widely respected data, published in July in the Journal of the American Medical Association, show that over a lifetime, 7.4 percent of women and 2.8 percent of men suffer major depression, the most serious form.

“Gambling is not depression. Some people who drink are depressed, but that doesn’t mean alcoholics are depressed,” she says. And if men are beating their wives, “they should stop, but I don’t think saying they are depressed is necessarily helpful.”

Even when questions are designed to avoid gender bias, she says, women suffer far more than men — in country after country.

But even psychiatric epidemiologists disagree about what counts as serious depression.

Dr. Alan Romanoski, a Johns Hopkins University psychiatric epidemiologist, agrees with Weissman that “it’s wrong to infer depression,” that is, a particular emotional state, just from observed behavior. “Life is tough enough trying to figure out the conscious world without trying to take on the subconscious, too.”

Take drinking — and the feelings presumed to underlie it. Psychiatrists used to think if someone could only understand why he drank, he’d stop, Romanoski says. But they had “no success whatsoever treating alcoholism and as a result, psychiatry fell into disrepute in the recovery movement and rightly so.”

But unlike Weissman, who studies lifetime rates, Romanski studies the prevalence of major depression at any given moment, and finds that, tallied this way, men and women suffer equally. But with clinically significant, though milder depression, things do get lopsided — with 8 percent of women and 3 percent of men affected, he says.

But other data seem to support Real’s belief that depression is widespread among males, including national suicide rates — 18.6 annually per 100,000 men, versus 4.4 per 100,000 women.

And figures from the National Center for Health Statistics, based on 1992 research by Harvard sociologist Ronald Kessler, suggest that over a lifetime, equal numbers of men and women — roughly half of each group — have some kind of psychiatric disorder, though this counts not just depression but anxiety and substance abuse as well.

Over a lifetime, Kessler says, 24 percent of women have a depressive disorder, versus 15 percent of men; for anxiety, it’s 31 percent for women, 19 percent for men. Substance abuse, however, affects 35 percent of men and 18 percent of women.

Gender differences in psychiatric illness are changing, he says, “but unfortunately for women, women are catching up more quickly in alcohol and drug problems than men are in depression and anxiety. If sex roles are involved, and they have to be in certain ways, it looks like changes in sex roles have led to worse problems for women relative to men.”

Still, Harvard psychologist Carol Gilligan finds Real’s thesis “very convincing.” Masculinity “is terribly restricting to men,” she says, in part because it implies “real men don’t get sad.” Part of depression is “about not being able to feel sad.”

Psychologist William Pollack, co-director of the Center for Men at McLean Hospital, also believes depression is vastly underdiagnosed in men. A 1991 Rand study showed doctors miss 67 percent of depression in men because they’re looking for what Pollack calls “feminized” symptoms like crying, not the irritability, anger and work “burnout” men often express.

And while Dr. Peter (“Listening to Prozac”) Kramer doesn’t agree totally with Real, he does agree that “undiagnosed depression in men wreaks havoc. They do all sorts of things rather than get treatment.” Depression, he adds, also “causes divorce as often as divorce causes depression, and I’d say more,” whichever spouse is depressed.

And there are those, like psychiatric epidemiologist Dr. Kostas Lyketsos of Johns Hopkins, who say the real “philosophic question is, is there bad in this world, and are there people who can’t be helped?”

Real answers this way: “The women’s movement and morally driven thinkers hold men responsible for bad behavior, but don’t hold men empathically. The men’s movement and psychology are tuned in to men’s wounding, but not the damage men inflict on others. My work is about holding men accountable for irresponsible behavior but holding them with empathy and love.”

The implication of Real’s message is that if men who act out would just get help, they — and the people around them — would be better off. But Lyketsos isn’t buying.

Imputing depression to men reminds him of the false memory debate in women, in which it was often taken as a given that a woman with psychological problems had been sexually abused and needed extensive therapy to dig out old “memories.”

“Nobody should be under the illusion that therapy is always good,” he says. With some people, it can “mess them up by creating a dependence and having them constantly question themselves.”

For men who really are depressed, though, the answer probably is to seek help. And for women involved with them, the first step is also to get the guy into therapy, if he’ll go. If he won’t, the next step, says Real, is to say, “If you don’t think you have a problem, then we have a problem as a couple and we need help.”

Often, it’s not the men who are “in conscious distress so much as the people who live with them,” he adds.

Still, Real argues, “the cure for covert depression is overt depression” and “intimacy is the ultimate cure for depression in men.”

This can be a tall order. “It’s a big pain in the butt to learn all this,” concedes Real. “Men would rather be left alone in some ways.

“But if you swallow the pill that you have to learn it, you’ll be happier and healthier, your family will be happier and healthier and you’ll live longer. Most men are not stupid. They understand this.”

Amen!

SIDEBAR 1:

More on depression:

About 70 percent of depressed people, men and women, are helped by antidepressant medications, and this rises to 80 percent or more when psychotherapy is added. Psychotherapy alone works as well as drugs for moderate depression, though it often takes longer.

Some common symptoms of depression and dysthymia (a less severe form of depression) include:

• Profoundly “down” or sad mood for several weeks or more.
• Diminished interest in regular activities.
• Sleep or appetite disturbances.
• Difficulty concentrating or thinking.
• Feelings of guilt, self-criticism or pessimism.
• Diminished energy.
• Suidical thoughts or behaviors.

If you think you or someone you love is depressed, you can contact your health care provider or the following organizations for information or referrals. (If it’s an emergency, go to the nearest hospital or call 911.):

• National Depressive and Manic-Depressive Association, 1-800-826-3632 or on the web atwww.ndmda.org. The Boston chapter, located at McLean Hospital, can be reached at 617-855-2795.
• National Mental Health Association, 1-800-969-6642
• National Institute of Mental Health, 1-800-421-4211. Ask for the DART (Depression Awareness,Recognition and Treatment) Program. On the web it’s www.nimh.nih.gov
• National Alliance for the Mentally Ill, 1-800-950-NAMI or 1-800-950-6264. The Massachusetts chapter, 1-800-370-9085
• The Center for Men at McLean Hospital, 617-855-2750
• Depressive and Related Affective Disorders Association, 410-955-4647, on the web atwww.med.jhu.edu/drada/
• You might also want to read about men and depression:
• “I Don’t Want to Talk About It,” by Terrence Real (Simon & Schuster)
• “New Psychotherapy for Men,” by William Pollack and Ron Levant (Wiley & Sons).(Due out in June.)
• “Real Boys,” by William Pollack (Random House).(Due out in May.)

SIDEBAR 2:

GENDER DIFFERENCES:

The rates of psychiatric disorders vary between men and women but overall incidence is similar

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