A true fish story

Fish breath may be the only side effect to the latest antidepressant.

Topics: Academia, Harvard,

Psychiatry is fishing for a breakthrough and it’s got something big caught
on its hook. If psychiatrists can reel it in, we might have a stunning new treatment
for depression and bipolar disorders: fish.

Fish oil to be more accurate. Omega 3 fatty acids to be exact.

In the first controlled, double-blind study of the effects of a dietary compound on psychiatric disorders, a Harvard psychiatrist has proved that omega 3 fatty acids alleviate depression and bipolar disorder.

Well, sort of.

He almost proved it. “Almost” was good enough for the National Institutes of Health to commission a $1.5 million follow-up study, and for Harvard to commit $100,000 for a separate test on depression.

“Almost” hasn’t gotten this kind of press since the “worst-to-first” Braves almost won the 1991 World Series. The stakes are so high, the evidence so strong and the implications so profound that nobody dares ignore the potential for omega 3 to revolutionize our understanding of the human brain.

“If omega 3 works, it would be one of the most exciting findings in psychiatry in the past 35 years,” says Jerry Cott, chief of adult psychopharmacology at NIH. Why? Because omega 3 isn’t just an antidepressant like Prozac or a mood stabilizer like lithium. It’s a dietary compound you can pick up at the grocery store. The profound implications don’t stem from omega 3′s apparent effectiveness in treating depression or bipolar disorder but from its seeming effectiveness in treating a whole range of brain disorders. Studies in England, for example, point to fish oil’s effectiveness on schizophrenia.

Right now, psychiatry has a pill for this and a pill for that, targeting different neurotransmitters and regulating their levels and activity. Omega 3 could conceivably wipe out this nickel-and-diming and bring forth a whole new currency in mental health.

The omega 3 study withstood scrutiny by the editors of the Archives of General Psychiatry. A peer-review analysis in the esteemed journal called the test a “landmark” in the study of dietary compounds on psychiatric disorders. But the buzz is preliminary. The findings must still be replicated in other studies.

Dr. Andrew Stoll, head of Harvard University’s psychopharmacology research laboratory at McLean Hospital in Belmont, Mass., is at the vanguard of a whole new wave of brain disorder research — testing dietary compounds and their effect on mood.



“I haven’t proved anything yet,” insists Stoll. No? Then why has he got himself, his wife, his kids, even his patients in private practice popping fish pills like after-dinner mints at an all-you-can-eat garlic buffet?

Because he won’t wait for proof of something he already believes in. All the patients in his private practice who suffer from bipolar and depression are on a regimen of omega 3 capsules along with their medications (lithium, antidepressants, etc.). Some of his patients aren’t on any medication at all. Just omega 3. And according to Stoll, they’re doing great.

Stoll is understandably skittish about letting the public know that he doles out perch as readily as Prozac. After all, he’s an assistant professor of psychiatry at Harvard University.

Though he’s afraid to start a stampede for something he can’t back up empirically, he backs up his argument with facts that are unchallenged by most scientists:

1) Omega 3s are basic building blocks critical to physical and cognitive development. They’re called “essential” fatty acids because the body does not make them. We get them through diet.

2) Today’s diet of saturated fats and processed foods has left us depleted of omega 3s. Current epidemiological studies and archaeological evidence of hunter-gatherer populations show dramatically higher levels of omega 3s than today’s Web-surfing, cell-phoning populations.

3) In industrial countries, rates of depression are accelerating and the age of onset is decreasing — even when statistical adjustments are made for self-reporting.

4) The biochemistry of omega 3s is remarkably similar to that of mood stabilizers such as lithium.

The important thing to remember about these four facts is that they mean squat. Correlation does not mean causation. No one has proved that eating more fish oil lifts depression. It is scientifically proven, however, that eating more fish oil dramatically improves cardiovascular health. That led Stoll to ask: If fish-eating cultures like those in Japan and Taiwan have the lowest rates of heart disease in the world, wouldn’t it follow that they’d also have the lowest rates of depression?

They do.

If a theory is a hunch with a college education, then Stoll had a world-class hypothesis: Maybe rising rates of depression and bipolar disorder are correlated with the sinking levels of omega 3s in our systems. Maybe diet is a key factor in maintaining mental health.

Stoll’s landmark test involved 30 people suffering from bipolar disorder. Half were given 14 capsules a day containing enough fish oil to make a gymnasium stink like a wharf rat; the other half were given 14 capsules of olive oil, the kind you use to sauti mushrooms.

Four months into the test, disaster struck. Even when treated with medications, bipolar disease has a high rate of recurrence as either depressive or manic episodes. “The rule of thumb in treating bipolar,” said Stoll, “is poly-pharmacy — several medicines at once.” Lithium may be the diva of the bipolar stage, but it shares equal billing with two co-stars the general public knows little about — Depakote and Risterdal. But despite the use of these drugs, recurrences are common.

The patients in the placebo group were doing so poorly they needed higher doses of their medicines. Eighty percent of the group relapsed into depressive or manic states. Giving them higher doses, however, meant ending the test (medicine levels must be kept constant or the results are skewed). Stoll was left with an ethical dilemma: Continue the test for the benefit of science or alleviate the pain and suffering of the control group. The test was ended.

Fortunately, Stoll had amassed enough data to show clinical significance. Only 14 percent of the omega 3 group had a manic-depressive recurrence compared to 80 percent for the control group. The test was measured by a Kaplan Meier survival analysis, a measurement devised for cancer research.

Stoll’s results raised eyebrows in the scientific community. A graph of the omega 3 group looks like the flat line of a cadaver’s EKG. Hardly anyone got sick. The control group looks like a staircase heading into the basement. Almost everyone got sick. The prophylactic effects of omega 3 were more than evident. “The data was strong,” said Stoll. “A lot of people believe it and that’s why we were funded for the follow-up.”

The NIH was impressed. So were the omega 3 patients. Most of them had never gone four months without a recurrence of a manic or depressive episode. So when the test ended, they continued with the omega 3 on their own, without clinical supervision.

Most test subjects were already on some kind of medicine. But eight subjects either couldn’t tolerate drug side effects or hadn’t found a medicine that worked. This is where the crashing thunder and organ music foreshadow the dramatic twist of the test: All four in the control group (no medicine, no omega 3) got sick. The four in the omega 3 group who weren’t taking any medicine? Not a single recurrence.

Another facet of the study that had many scientists scratching their heads was the marked decrease in depression within the omega 3 group. Lithium and Depakote prevent mania but they’re not so good at treating depression. “In fact,” said Stoll, “the biggest problem with bipolar disorder isn’t the mania, which we can treat pretty readily, it’s the depression. Depression happens most often, lasts longer and is more disabling, triggering higher suicide rates.”

If omega 3 is so similar to lithium and lithium isn’t very good at treating depression, then why was the Hamilton Rating Scale (a screen for depression) so much lower in the omega group? That’s a good question. Harvard is ponying up $100,000 to find the answer.

Stoll is excited about this “accidental” finding. “Science consistently discovers drugs by accident,” he said, “and works backwards from there.” One of the first antidepressants ever discovered was designed for treating tuberculosis. “Doctors noticed not only that their patients recovered from tuberculosis, but they also noticed how much happier and functional they were,” recounts Stoll. And thus was born a whole new class of antidepressants — MAO inhibitors.

So why does omega 3 seem to have an effect on brain disorders? The consensus is that omega 3 is incorporated into cell membranes, making them more fluid. Every cell membrane has a layer of fat around it. Receptors stick out of the cell. They go from the inside of the cell all the way to the outside of the cell. They float in that membrane of fat. If the cell covers its privates with fat from double-cheese Whoppers, extra fries and chocolate milkshakes, it’s going to make the receptors inflexible. Receptors are like the satellite dish in each brain cell, picking up neurotransmitter “signals” like serotonin, dopamine and norepinephrine from other brain cells. Imagine how your TV reception would be if your satellite dish couldn’t move to capture the signal.

“Think of lard vs. oil, which is liquid at room temperature,” explains Stoll. “If you don’t have a good diet, your membranes are going to be physically stiff, which changes receptor dynamics, changes ion channels and what calcium does in the cell.” It appears that omega 3 works by allowing receptors to function smoothly. Emphasis on “appears.” No one really knows.

Brain disorders such as depression are caused not simply by an excess or lack of neurotransmitters like serotonin, but a complex abnormality in what Stoll calls “cell signal transduction pathways.” That means an abnormality in any of the thousands of events happening between the transmission, reception and post-reception of neurotransmitters. That includes the cells, the cell membranes, the receptors, the neurotransmitters, the whole shooting match. Something somewhere in these pathways is breaking down and nobody knows for sure what it is.

Basically, with selective serotonin reuptake inhibitors and other medications, psychiatry is just moving furniture around in a rickety building. But what if it discovered the support beams stabilizing the entire structure? It’s a big if, but a lot of hard-nosed scientists believe it will come to pass. Stoll’s test had too many limitations for the hopes about omega 3 to be labeled a certainty. It was a relatively small sample, it ended too soon and the patients were all on different medications. But Stoll isn’t the only scientist testing omega 3. Several studies abroad showed equally promising results. Currently, the Stanley Foundation in Virginia is conducting three separate tests. But it will be years before anything is known definitively.

And that’s what makes Stoll’s private behavior so curious. Publicly, he says the data on omega 3 does not constitute proof, but privately he behaves like he’s preparing for the second coming of psychiatry. He gives omega 3 to his family and patients. And his wife, also a physician, just started a company selling a highly concentrated solution of omega 3 not available in health food stores.

And it’s not just Stoll swooning with fish fever. It’s Cott from the NIH as well. Cott does not believe that anything has been proved scientifically, either. So why is he taking three grams of omega 3 a day?

There’s something odd about scientists advocating restraint in public and then making a mad dash to the health food store when nobody’s looking. Are brilliant scientific minds just as vulnerable to hope and hype as the rest of us? Or do they know something they’re not telling us?

Cott acknowledges that a number of psychiatrists, like Stoll, prescribe omega 3 for their patients and have seen remarkable results. But “open label” studies (where the doctor and patient both know what’s being prescribed) are dismissed in the scientific community, and rightfully so, according to Cott. “Open label” automatically introduces bias. Without a control group, results aren’t facts; they’re anecdotes. And the worst kind, too, because they’re bloated with placebo effects.

So why do scientists take omega 3 when they profess nothing’s been proved?

“Look,” said Cott, “there’s a risk/benefit ratio to everything you take. You balance the known risk with the known benefit. A supplement like omega 3 has zero risk and an unknown benefit. How can you lose?”

Cott takes three grams of omega 3 per day — the equivalent of eating salmon once a day.

He buys it in bulk at Costco.

Michael Alvear is the author of "Men Are Pigs But We Love Bacon," a collection of his sex advice columns, to be published by Kensington Press in May. He lives in Atlanta.

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