Feeling depressed? Ask not what your parents did or didn’t do when you were a child. Ask yourself what you had for dinner last night, and the night before, and the night before that.

For half a dozen years now, the evidence has been growing that omega-3 fatty acids, the kind found in fatty fish like salmon, sardines and tuna, can help prevent and treat depression.

Rich in EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), these are among the “good” oils that have long been known to reduce the risk of heart attacks and strokes. They are also the oils that, in recent decades, in tandem with rising depression rates, Americans have not been getting enough of.

The case for linking low omega-3 levels to depression is strong, though not yet a slam-dunk. But there is little risk -and significant benefit – to following the American Heart Association recommendation to eat fish at least twice a week and, if you already have heart disease, taking at least 1 gram a day of supplements containing EPA and DHA. Unlike omega-6 fatty acids (from corn and safflower oils), which most of us overindulge in, omega-3s combat auto-immune diseases like rheumatoid arthritis , reduce cardiac arrhythmias and are crucial to the development of the spinal cord, brain and retina in infants and to healthy brain functioning in adults as well.

The latest evidence for the role of omega-3 fatty acids and depression came several weeks ago last month, when researchers from McLean Hospital in Belmont, reported that omega-3 fatty acids, plus uridine, another substance found commonly in food, prevented depression in rats just as well as antidepressant drugs. The effect of uridine was immediate, said Bill [cq] Carlezon [cq], director of the behavioral genetics lab at McLean. It took 30 days for omega-3 to kick in. But combining the two made omega-3 effective three times faster.

“There is something to this story,” said Dr. Andrew Leuchter [cq], vice chair of psychiatry at the Neuropsychiatric Institute at UCLA. “I have seen enough patients who treat themselves with omega-3 fatty acids to think these substances may have, at least in some individuals, potent effects on mood.”

No one knows exactly why omega-3s might protect against depression, but theories abound. One is that depression may, in part, be an inflammatory problem, which omega-3s can damp down, said Dr. Andrew Stoll, [cq], director of psychopharmacology at McLean. Another is that the oils keep cell membranes more fluid, making it easier for receptors to respond to neurotransmitters like serotonin, which is often deficient in depression. Another is that omega-3s may boost levels of serotonin.

Whatever the underlying mechanism, “the epidemiological evidence is huge,” Stoll said, that omega-3s can protect against depression.

Overall, major depression is 60 times more prevalent in countries where little fish is eaten, said Dr. Joseph R. Hibbeln [cq], senior clinical investigator at the National Institute on Alcohol Abuse and Alcoholism.

 In 1998, Hibbeln and others showed that high fish-eating countries like Japan and Taiwan have very low rates of depression, while low fish-eating countries like Germany and the United States have high rates. “When you compare rates of depression across populations, there is a consistent finding of strikingly lower rates of major depression, bipolar depression, seasonal affective disorder and postpartum depression in countries where people eat more seafood.”

A 2002 double-blind, placebo-controlled study of 20 people in Israel, for instance, showed that adding EPA to standard antidepressants significantly decreased depression after three weeks. A 2002 Scottish study of 60 people came to similar conclusions when patients added a 1-gram daily supplement of EPA to their standard treatment. (Interestingly, higher doses did not work as well.) A 2002 Taiwanese study of 28 people using both EPA and DHA also found significant improvement in depression scores, compared to placebo.

But not all studies support this. A New Zealand team studied 77 mildly depressed people and randomly assigned them to add 8 grams a day of fish oil or a placebo (olive oil) to standard antidepressant therapy. Mood improved in both groups.

A Finnish study that asked nearly 30,000 men to recall their fish oil consumption over the years also found no link between omega-3 fatty acids and depression or suicide, although studies based on recall are notoriously inaccurate. And a double-blind, placebo-controlled study of 35 people at Baylor College of Medicine in Houston found no improvement in depression when they gave patients only DHA, not EPA.

In the plus column, bi-polar depression, too, also known as manic-depression, also seems to be helped by omega-3 fatty acids. A study comparing 10 countries showed that higher fish consumption correlated with lower rates of bi-polar disorder. A 1999 study by Stoll of McLean showed that giving fish oil supplements to people with bi-polar disorder reduced episodes of depression and mania.

Omega-3 fatty acids also appear to reduce hostility and homicide. Several studies have found that low intake of fish and omega-3s correlates with higher rates of hostility, which is often associated with depression in males. A 36-country study showed lower rates of homicide in countries where people ate more fish.

And postpartum depression also appears linked to omega-3 levels. A study of women in 23 countries showed that women who ate less seafood and had lower rates of DHA in their breast milk were more likely to suffer postpartum depression. Pilot studies by Dr. Marlene Freeman [cq], director of the Women’s Mental Health Program at the University of Arizona, suggest taking DHA and EPA can reduce post-partum depression by 50 percent.

(Many pregnant women and nursing mothers, added Freeman, have been frightened about eating any kind of fish because of government warnings of particularly high mercury levels in a few species, king mackerel, shark, swordfish and tilefish. The Center for Science in the Public Interest, a nutrition advocacy group, says that sardines and salmon contain little mercury; women of reproductive age should probably limit their consumption of canned tuna to one can of white or two cans of light per week.)

Even borderline personality disorder, characterized by volatile interpersonal relationships and impulsivity, seems to respond to omega-3 treatment. Yet another McLean study of 30 patients found that EPA, without any other medication, improved symptoms of borderline personality.

That’s more than enough evidence for me. Given the longstanding overall health benefits of omega-3 fatty acids and the newly-emerging psychiatric benefits, the conclusion is a no-brainer. Eat fish three times a week. And if you hate fish (as I do), take at least one gram a day of a supplement with EPA and DHA.     

The sophisticated science of brain scanning may be on the brink of revolutionizing the intuitive art of psychiatry, one of the few domains left in medicine in which a doctor’s educated guess is still the most common way to figure out what’s wrong

To be sure, brain scanning is still too young a science to be used for routine diagnosis of the most common psychiatric ills. But it is already proving invaluable in understanding the underlying abnormalities in a wide range of psychiatric disorders including obsessive compulsive disorder (OCD), schizophrenia, anxiety and depression.

Obsessive-compulsive disorder, for instance, which strikes roughly 8 million Americans, is a potentially disabling condition in which recurrent fears, images or impulses cause severe anxiety and drive people to repetitive behaviors such as compulsive hand-washing, arranging, checking or hoarding.

At the University of California, Los Angeles, doctors are experimenting with PET (positron emission tomography) scanning to predict which patients with OCD or major depression will respond to the anti-depressant drug, Paxil, and which won’t.  (In PET scans, patients are given a radioactive form of the sugar, glucose; the color-coded images show, in real time, which areas of the brain are using the most glucose and are working hardest.)

One patient in the UCLA study, Marc Pincus, is a 41-year old office manager who used to wake up at night and feel he had to turn his head toward the clock exactly 19 times (once for each family member) within one minute to protect them from disaster. “If, by chance, the clock changed, I had to start again. So I didn’t get a lot of sleep,” recalls Pincus, who knew this was not protecting anyone but felt he had to do it anyway.

Just as Pincus’ initial PET scan predicted, he had a good response to Paxil. A second PET scan after several months on the drug showed the characteristic changes of a good response to the drug.

The lead researcher, Dr. Sanjaya Saxena, an associate professor at the UCLA Neuropsychiatric Institute, says that PET scans have “the potential to be used for identifying patterns of brain activity that predict response” to therapy for both OCD and depression, even though the scans confirmed that the underlying brain abnormalities in OCD and depression are different.

At Massachusetts General Hospital in Boston, Dr. Scott Rauch, director of psychiatric neuroimaging, has long been using PET and other scans in psychiatric illnesses. In OCD, he and his colleagues scan patients first, while they are resting, then they touch them with feared objects that induce obsessions.

 “You see the circuitry light up,” says Rauch, noting that the abnormal brain circuits involve nerve pathways from the orbitofrontal cortex (behind the eyes) to the caudate nucleus (part of the basal ganglia) and thalamus, which lie deep within the brain.

Rauch and his colleagues have also shown that abnormal neural activity in the anterior cingulate portion of the OCD pathway can predict how well people with severe, intractable OCD respond to surgery in which doctors interrupt the pathways through tiny cuts.

Armed with patients’ scans, brain surgeons are now  trying a potentially better approach – implanting permanent electrodes (brain pacemakers) into the abnormal brain tissue to modulate the abnormal electrical activity, a technique, called deep brain stimulation, already being used to treat Parkinson’s disease.

More than 15 patients with severe OCD have received the implants from doctors in a multi-center study based at the Cleveland Clinic in Ohio, Butler Hospital in Providence, R.I. and the University of Leuven in Belgium.  The electrodes, made by Medtronic, Inc., can be turned up or down by the doctor, making the procedure is reversible – unlike traditional neurosurgery.

Dr. Ali Rezai, director of functional neurosurgery at the Cleveland Clinic, says patients who have had the electrodes implanted show an average 35.7 percent improvement in OCD symptoms.  At Butler Hospital, Dr. Benjamin Greenberg, who heads the brain stimulation work in OCD, says that while longer follow up is needed, initial results seem “promising.” The researchers are also trying deep brain stimulation for intractable depression.

Elsewhere, researchers are using other types of scans to probe other psychiatric afflictions. At the National Institute of Mental Health, researchers have used MRI, or magnetic resonance imaging, to study ADHD, or attention deficit hyperactivity disorder in children. (In MRI, a magnet induces chemicals in the body to emit characteristic radio signals. These signals are converted into 3-D images that show the anatomical structure of the brain. No radioactive drugs are needed.)  They found their brains to be 3 to 4 percent smaller than those of normal children.

Other researchers are using a variant of MRI called fMRI, or functional MRI, to study brain abnormalities in schizophrenia and other disorders. (Functional MRI provides a real-time image of the brain’s functions, not just structure, by tracking blood flow.) 

At Johns Hopkins University, Dr. Rudolf Hoehn-Saric, a professor emeritus of psychiatry, is using fMRI to compare the brains of normal and anxious people. In tests involving listening to recordings of personal worries, people with generalized anxiety disorder, his research shows, have increases in activation in parts of the prefrontal cortex (the thinking part of the brain) and in parts of the emotional brain, or limbic system, including the hippocampus.  But after seven weeks on the medication Celexa, an anti-depressant, the patients’ scans improved considerably, says Hoehn-Saric.

In fact, many of the drugs, like Celexa, that were originally designed to combat depression also seem to work for anxiety, which raises a question the imaging scientists haven’t quite answered yet.

 “We know that anxiety and depression, while distinct syndromes, have certain common clinical features and both respond to similar drugs,” says Dr. Helen Mayberg, chair of neuropsychiatry at the Rotman Research Institute at the University of Toronto. “Interestingly, when we get to scanning, we can see at the brain level what might account for some of these similarities and differences.”

In other words, brain scans may never substitute for intuitive guesswork by a good psychiatrist. Nor should they.  But they will undoubtedly be increasingly useful in helping doctors figure out which patients with severe psychiatric illnesses are most likely to respond to treatments.

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.”

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.”

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.”