Prozac of the sea

( Psychology Today ) Potera, Carol; 05-15-1996

It’s the one nagging drawback to the low-cholesterol bandwagon (besides having to give up cheese omelets, of course). For all the benefits that cutting cholesterol bestows on the heart, researchers have linked such diets to higher rates of depression and suicide.

A few studies, though, find no connection between cholesterol and mood. And the explanation may lie in the type of polyunsaturated fat we eat, rather than cholesterol itself.

“When your doctor tells you to lower cholesterol, you usually lower your fat intake,” observes Joseph Hibbeln, M.D., a psychiatrist at the National Institute of Alcohol Abuse and Alcoholism. Trouble is, a low-fat diet can deprive us of some fats, called essential fatty acids, that are required to keep our nervous and immune systems healthy. One of these is docosahexaenoic acid (DHA), an important component of brain cell membranes.

While our bodies can synthesize most fats, we must obtain essential fatty acids like DHA from food. Fish is an especially rich source of DHA, a type omega-3 polyunsaturated fat.

But it’s not simply the amount of omega-3 in our diet that matters to our brains, Hibbeln suggests in the American Journal of Clinical Nutrition (Vol, 62, No. 1). What may be important for good mental health is the amount of omega-3 relative to a related fat, omega-6, that is found in corn and soybean oil. Too much omega-6 in our bodies, in tandem with too little omega-3, could increase our risk of depression. If that’s the case, cholesterol may merely be an innocent bystander.

It would also mean that eating omega-3-laden fish and curbing our intake of omega 6 sources 6 might actually help protect us from depression and suicide. Indeed, in countries where folks eat lots of fish, like Taiwan and Japan, the depression rate runs 10 times lower than in North America. And when cholesterol and fat were lowered in one study by replacing animal fat with fish, depression improved rather than worsened. But in most cholesterol studies, people replace animal fats with corn oil, which the body cannot convert to DHA.

Hibbeln stresses he’s not advocating that anyone change their diet just yet. But a rapidly growing body of research suggests that for cardiovascular health, not all polyunsaturated fats are created equal. It might be wise to balance the amount of each variety we eat, just as we juggle the overall proportions of fats, carbohydrates, and protein in our diet. “These issues are important to the heart,” says Hibbeln, “and they’re probably also important to the mind.”

Insight meditation found to relieve psoriasis, anxiety

Medical Post
David Hodges
05-16-2000

Combining yoga, meditation, body scans and dharma talks as treatment shows success TORONTO – Evidence is being gathered to suggest that mindfulness-based stress reduction (MBSR)-a form of insight meditation-may reduce psoriasis.

Research presented at the meeting here suggested that MBSR intervention enhanced rates of skin-clearing in patients with psoriasis undergoing phototherapy (UVB) and photochemotherapy (PUVA).

MBSR is a program which consists of a combination of meditation, yoga, body scan (a type of relaxation training protocol) and dharma talks (lectures that encourage a sense of peace and feelings of love).

Findings for the psoriasis study came from an article published in the journal Psychosomatic Medicine in which 37 patients were assigned to receive UVB and PUVA therapy for the treatment of moderate to severe psoriasis. Patients were divided into two groups, in which some received MBSR and others did not.

At 125 days, both of these groups had attained the same rate of skin clearing, but it was noted that the intervention group who received the MBSR treatment got better much more quickly than those patients who did not receive the MBSR treatment.

How this effect works, however, is not clear.

“Basically speaking, we don’t know,” said Dr. Greg Dubord, director of the Canadian branch of the National Council for Reliable Health Information and founding director of the Rational Alternative Medicine (RAM) Institute.

“Most of this mind/body stuff is speculation, and we really don’t know the exact intervening steps.” Nonetheless, MBSR is working quite well, he added.

Other studies involving MBSR have shown a 50% reduction in chronic pain and anxiety, Dr. Dubord said.

In one such study that examined the clinical use of MBSR for the self- regulation of chronic pain in 90 chronic pain patients, researchers reported that statistically significant reductions in a variety of pain-related measures were seen among patients receiving MBSR while a control group showed no improvement.

Followup of 2.5 to 48 months showed good compliance among the patients who received MBSR, and that gains were maintained.

Another study designed to determine the effectiveness of MBSR in the treatment of patients with generalized anxiety disorder or panic disorder with or without agoraphobia showed significant reductions in anxiety and depression scores after treatment for 20 of the 22 patients involved in the study; no control group was used. A three-year followup of 18 of the 22 original subjects showed that gains were maintained.

Today, MBSR is being used and studied in various centres around the world, particularly in North America, Dr. Dubord said.

The Buddhist meditation practice is used in a number of centres in Toronto, including mainstream centres such as the Toronto Hospital where there is an MBSR clinic, he added.

Laughter CD for Depression on Sale in Austria

By Michael Leidig
VIENNA (Reuters Health) Nov 27 2002 – A compact disc of people laughing, produced by the Austrian society for depression-related illnesses (OeGDE), has gone on the market in Europe in a serious bid to help patients “see the brighter side of life.”

The CD is a 20-minute compilation of what the makers describe as “infectious laughter and motivation-boosting statements by celebrities.”

Dr. Hermann Koutek, from the OeGDE, told Reuters Health that they wanted to give those with depression something to laugh about.

“When someone is really depressed, there is usually nothing in their lives to laugh at. We wanted to produce something simple but effective that people can easily turn to when they want to be cheered up,” he said.

He said the CD should be treated seriously and was not just a gimmick.

“There has been solid scientific research behind the CD. The people who come for help at the OeGDE usually suffer from severe depression. They can neither laugh nor cry. They are empty inside and cannot express any emotions, whether positive or negative. They simply do not care.”

“The process of bringing depressed people out of this despondency has to be a slow and sensitive one. We have found a laugh is infectious. It can lift somebody out of a deep depression, even if it is only for a little while–but it’s a good start,” he said.

Dr. Koutek added that a CD of laughter is much more likely to work than other laughter- inducing experiences because it is only directed at one of the senses and is less likely to cause offence.

“Depression sufferers are very sensitive, they cannot be overburdened with sounds, images or feelings, which is why the CD works. Sound is much easier to take in than pictures. Music is also good as a first step to recovery, but not all will have the same uplifting effects as laughter.”

Dr. Koutek added that the CD worked best when used alongside prescribed medicine. “Medication is also needed for long-term recovery,” he said.

The CD, which is currently only available in German, features the laughter of a number of Austrian celebrities, including Olympic ski champion Michaela Dorfmeister, singer Reinhardt Fendrich, Governor of Lower Austria Erwin Proll and former star footballer Tony Polster.

Dr. Koutek said that he would also be interested in making laughter CDs for foreign language markets. He said: “As far as I am aware, this is the only such CD in the world. It would be a great step in the battle against depression, it transcends borders.”

The OeGDE is an Austrian-based physicians’ organisation founded 2 years ago. It provides help and information on depression-related illnesses to both doctors and patients, and promotes home visits to housebound patients. The society is also hoping to expand across borders. Dr Koutek said: “We have looked for similar associations the world over but have been unsuccessful. There are many self-help groups, but these usually aren’t supported by professionals. We would very much like to set up a network of similar organisations across Europe and eventually all around the world.”

Healing any doubts over ‘natural’ therapy

Evening Telegraph
Catherine Turner
12-04-2000

THE House of Lords has called for the booming complementary health industry to be brought under full regulation after a 15-month inquiry uncovered an alarming lack of regulation and poor scientific research. Feature writer CATHERINE TURNER asked therapists at a natural remedies clinic in Coventry for their reaction.

HOMEOPATH Kathy Stranks believes legislation to protect the public from quack complementary practitioners is long overdue.

The Lords select committee on science and technology has recommended that natural remedy therapists should be trained and registered so they can be struck off if incompetent, like traditional GPs.

“I think it is very important, essential even, that complementary therapies are properly regulated. All practitioners have a responsibility to be well-educated,” said the 52-year-old former nurse from Napton, near Rugby.

“In my opinion the best solution would be to have an umbrella group, like the British Medical Association, with separate professional bodies within that.

“It has been claimed that there is no serious evidence-based research into the effectiveness of complimentary therapies.

“But Bristol University runs a degree course in complementary medicine and they have done some fantastic research with medical professionals.”

Kathy is one of eight therapists who work at Alda House, a co-operative natural therapy centre in Manor House Drive, Coventry.

It was founded in 1994 by Linda Stokes.

Therapies include acupuncture, aromatherapy, chiropody, holistic facials, homeopathy, Bach Flower Remedies, chiropractic, reflexology, reiki, sports massage, stress management, therapeutic massage and Hopi ear candles.

Linda, aged 53, said: “The therapists who work here are all qualified, they are registered with a professional body and have full insurance.

“I agree with Kathy, we should have some sort of legislation.

“With this in place people who are unqualified will quickly disappear.

“My thoughts are there has been a lot of scare-mongering – complementary remedies can be just as safe and effective as conventional medicine.

“My 18-month old grandson had homeopathy to cure a bad chest.

“I do not like the word alternative therapy, I always use complementary because everything we do complements orthodox medicine.”

Linda first became interested in complementary medicine after undergoing major surgery 12 years ago.

One of her friends badgered her to see a therapist – she went and was surprised by the results.

The mum-of-two from Coventry said: “It was quite amazing because in complementary medicine the main belief is that the emotions are linked to the physical.

“This lady I saw traced the problem back to when I was 10 years old when my father was killed in a road traffic accident.

“The imbalance in my energy levels had caused my resultant health problem.

“She specialised in kinesiology (the study of the mechanics of body movement) and was so accurate.

“My recovery greatly improved. It made me think there’s got to be more to this.

“I did an aromatherapy course, a reflexology course and Bowen Technique. I also run baby and infant massage classes.

“I am one of two women in the UK qualified to teach Indian head and ear healing with Hopi candles.”

Homeopathy is an entire body and soul repair

SINCE she was a child Kathy Stranks realised that she had psychic powers.

Her natural ability has led to a 40-year interest in para-psychology, a subject which she has lectured on at Birmingham and Warwick University.

Kathy, who qualified as a nurse before she had her four children, said: “People have thought I was barking mad since I was 12.

“I do simple readings – tarot, I-Ching or old-fashioned palm reading. My father was the same.

“I am quite good at understanding where people are coming from.

“I find people’s hands fascinating. You can tell such a lot, even with my own friends I can see different aspects of their character I didn’t know existed.

“I’m a problem solver when it comes to emotions. I have worked with Relate and so I have experience of dealing with relationship issues.

“I decided to do homeopathy, because it offers an integrated approach. It gives support on an emotional level which allows people to deal with any health problems. It’s entire body and soul repair. ”

Kathy studied homeopathy part-time at a college in Devon over five years after her children had grown up.

Homeopathy is based on the natural Law of Similars, discovered by German physician Samuel Hahnemann 200 years ago.

It works on the principle that disease can by cured by a medicine, which when given to healthy people produces similar symptoms to the disease.

When you go for a consultation the homeopath will spend time getting to know all about you – your lifestyle, past health, your family and about your illness.

After your case has been carefully considered you will be prescribed a remedy, usually in the form of pills which are easy to take, non toxic and not habit forming.

It occasionally happens that your symptoms may appear worse for a little time – but this is a good sign and shows Homeopathy can be used as an alternative treatment in pregnancy, for children’s health problems such as ear aches, asthma and eczema.

It can also help arthritis, hypertension, hayfever allergies, menstrual and digestive disorders and emotional states such as grief, trauma, depression and anxiety.

Kathy said: “I first went to a homeopath because I had 12 tooth abscesses – and they wouldn’t go away.

“The dentist said ‘we’ll have to take your teeth out’. But I thought there must be something else I can do.

“I found a homeopath. I took one tablet and my face went up like a balloon. I was so shocked I rang her up and she said: “It’s OK, it’ s a good sign”.

“I found out the abscesses were caused by loose mercury floating around my mouth.”

The consultation fee is pounds 45, and follow up visits are pounds 32.

COMPLEMENTARY THERAPY GUIDE
ACUPUNCTURE Small needles inserted into the body to stimulate nerve impulses

AROMATHERAPY A full body, face or back massage with up to three specially chosen plant oils. A great stress buster but also effective in combating cellulite, eczema, psoriasis, sinusitis and muscle tension.

BOWEN TECHNIQUE A simple hands-on therapy that involves gentle movement of the muscles. Suitable for sports injuries, RSI, frozen shoulder, neck and back pain.

CHIROPRACTIC Massage techniqueused to treat muscle and joint complaints HOPI EAR CANDLES Hopi ear candles are a hollow candle made from essential oils, herb and spices. A candle is placed in the ear and burnt, allowing the vapours to travel into the ear to clear any congestion of thesinuses. After the treatment you have a facial massage.

REFLEXOLOGY Foot massage, used primarily to relieve tension and improve blood supply REIK Natural Japanese healing system. The practitioner places their hands non-intrusively in a sequence of positions which cover the whole body. Suitable for all conditions whether they are physical, mental or emotional.

Treatments range from pounds 10 to pounds 45.

Can Taped Goggles Heal Emotional Disorders?

Wednesday, October 21, 1998
(This is an unedited, uncorrected transcript.)

From ABC’s 20/20

SAM DONALDSON: Tonight, we bring you word of an amazing medical discovery. It’s not a bio-engineered drug or a dazzling piece of high-tech equipment. This is a breakthrough treatment for depression and anxiety that is so simple, even the Harvard doctor who came up with the idea couldn’t believe it would work. Our own DR TIMOTHY JOHNSON: turns the spotlight on this cutting-edge therapy-a pair of goggles and some tape, giving some patients a dramatically different view of the world.

DR TIMOTHY JOHNSON, ABCNEWS MEDICAL EDITOR (VO)
Depression and anxiety-what is the key to unlocking the troubled mind? Psychologists believe in the healing power of talk therapy. Neuroscience, on the other hand, tells us that emotions are generated by brain chemistry and that drugs like Prozac are, therefore, crucial. But now, Dr Fredric Schiffer, a Harvard psychiatrist, has come up with a startling new concept to explain some common emotional disorders. And he says he’s found a safe, cheap and surprising way to help treat them-a simple pair of goggles, seen here in a college class demonstration. These ordinary goggles are taped so that a person can see only out of the extreme left side, and these goggles allow the person to see only to the extreme right. Dr Schiffer says that the light from looking out just one side activates the opposite side of the brain, and, therefore, triggers thoughts and emotions specific to that side.

DR FREDRIC SCHIFFER, PSYCHIATRIST: I’m so amazed at this.

DR TIMOTHY JOHNSON: (VO): So are his patients. This patient agreed to talk to 20/20 if we did not identify him. We’ll call him “Joe.” Three years ago, JOE: felt himself slipping dangerously into depression. The pressures of a new job had quickly overwhelmed him. The anxiety he felt was intense and painful. He tried one medication after another, but nothing worked.

JOE, GOGGLE THERAPY PATIENT: When you’re depressed and you’re severely depressed, one of the things that seems to disappear is hope.

DR TIMOTHY JOHNSON: (VO): He says the first time he tried on the goggles in therapy, they dramatically lifted his dark and pessimistic mood.

JOE: It was such an immediate difference. It was startling. And this was the very first time.

DR TIMOTHY JOHNSON: (VO): Dr Schiffer, who is on the staff at the world-famous McLean Hospital in Boston, believes, like many people do, that we often have two sides to our personalities-one that’s more calm and accepting, another that’s more emotional and impulsive.

ANGRY MAN: It’s insane.

DR TIMOTHY JOHNSON: (VO): But he takes it one giant step further. In his book, “Of Two Minds: The Revolutionary Science of Dual-Brain Psychology,” he argues that sometimes we literally have two different minds in our brain-a calm, optimistic mind on one side, and an anxious, pessimistic mind on the other. Dr Schiffer says visual stimulation with the special goggles he uses in therapy can activate one or the other side of the brain and therefore trigger either the calm and optimistic mind or the anxious and pessimistic mind. Dr Schiffer says the glasses help his patients get better by calling on their calm mind to help teach their anxious mind. (on camera) So the glasses, really, through the eyes, help to isolate one part versus the other part.

DR FREDRIC SCHIFFER: It’s to get the healthy part to help the troubled part.

DR TIMOTHY JOHNSON: Looking left or right in order to change our feelings or emotions is controversial. Some neuroscientists are skeptical. But many other experts believe that Dr Schiffer’s theory is a logical extension of past studies showing that the two halves of our brain function quite differently. In other words, if our two halves can function differently, maybe they can feel differently. In 1995, Dr Schiffer decided to test that theory with an admittedly very low-tech experiment.

DR FREDRIC SCHIFFER: I decided to put my hands over my eyes like this to see if I felt a little different that way versus that way.

DR TIMOTHY JOHNSON: (on camera) Yeah?

DR FREDRIC SCHIFFER: And I didn’t feel any different. But I went to the office that afternoon and, not expecting anything, I asked a patient to do it.

DR TIMOTHY JOHNSON: Figured it wouldn’t hurt. Might be worth trying.

DR FREDRIC SCHIFFER: Yeah, it wouldn’t hurt. And the patient says, “Oh, my God.” I said, “What’s the matter?” He says, “I got all my anxiety back.” And he was a guy who had come in six months earlier for anxiety, and he was doing much better. And so, I quickly said, “Well, try the other side.” And he said, “Oh, that feels good.” So I was amazed. I was absolutely amazed.

DR TIMOTHY JOHNSON: (VO): All five of Dr Schiffer’s patients that day had similar dramatic responses. So just two days after the first attempts with patients using hands in his office, Dr Schiffer tried using taped goggles instead.

DR FREDRIC SCHIFFER: The patients would tell me how far to put the tape over, and they’d say, “No, that’s not as strong.” And I’d move it over a little more. “Yeah, that’s better,” and …

DR TIMOTHY JOHNSON: (on camera) So you’d experiment with them?

DR FREDRIC SCHIFFER: Yeah. They would literally give me feedback, and it was very accurate and consistent.

DR TIMOTHY JOHNSON: (VO): The next step was to test the goggles more scientifically. Dr Schiffer tested emotional responses in 70 patients while provoking different feelings with the right or left-sided goggles. He noticed that some had the anxious and pessimistic feelings in their left brain, others in their right brain. It would vary from one individual to another, and it was difficult to predict which side had which feelings until he tested them with the goggles. He also used brain wave studies in 15 test subjects to demonstrate that left-looking goggles, indeed, aroused the right brain and vice versa. I observed a volunteer test subject, a college student named Chris. It was his first time trying the special goggles. Neuroscientist Carl Anderson (ph) asked CHRIS: to rate how anxious he felt while looking out goggles that were taped to allow him to see only out of the extreme right side.

CARL ANDERSON, NEUROSCIENTIST: How much anxiety do you feel now? None at all, mild amount, moderate amount, quite a bit or an extreme amount?

CHRIS: I want to say an extreme amount.

DR TIMOTHY JOHNSON: (VO): CHRIS: also reported that he felt extreme tension and anger while looking to the right. But when he put on goggles that let him look out the left, his reactions were quite different. When asked to rate his anxiety level …

CHRIS: I don’t want to say I feel like none, but I don’t feel like really anxious.

DR TIMOTHY JOHNSON: (VO): Dr Schiffer asked CHRIS: to retry the right-looking glasses that seemed to provoke him.

DR FREDRIC SCHIFFER: Tell me what you’re feeling.

CHRIS: I’m feeling like I want to take these glasses off.

DR TIMOTHY JOHNSON: (on camera) Because?

CHRIS: They’re making me angry.

DR FREDRIC SCHIFFER: Now I want you to try this other pair again.

CHRIS: OK.

DR TIMOTHY JOHNSON: (VO): These glasses allow CHRIS: to again see out the left side, and they seem to comfort him.

CHRIS: This side feels more easy-going, more happy-go-lucky kind of personality. The other side, I kind of feel like I want to go to war or something.

DR FREDRIC SCHIFFER: Go to war?

CHRIS: Yeah.

DR TIMOTHY JOHNSON: (VO): What CHRIS: has just demonstrated in the lab is what Dr Schiffer says he’s observed in his patients. Their psychological suffering seems to be located more profoundly in one side of the brain than the other. I had the opportunity to sit in on a therapy session with Joe, the patient we met earlier. In previous sessions, he had learned how his two brain sides differ.

DR FREDRIC SCHIFFER: Why don’t you pick a pair?

JOE: These? Well, the negative side first?

DR TIMOTHY JOHNSON: (VO): For Joe, the negative side is in the left brain. I observe how quickly Joe’s distress sets in.

JOE: It immediately puts you in an uncomfortable situation.

DR FREDRIC SCHIFFER: What are you feeling?

JOE: Anxious. I’m a walking advertisement for, you know, just insecurity and ultimately failure at what I’m setting out to accomplish. And it manifests itself in anxiety because I don’t want to feel that way.

DR FREDRIC SCHIFFER: It sounds very painful.

JOE: Yes, it is. Life would be intolerable if you had to live it constantly out of this one side.

DR TIMOTHY JOHNSON: (VO): Dr Schiffer now asks JOE: to switch to the positive goggles. I can see the anxious expression on Joe’s face change immediately.

JOE: See, it never ceases to amaze me. Right now-and I always chuckle with you when this happens. I mean, despite that we’ve been together for a while. I mean, I still get a kick out of it.

DR TIMOTHY JOHNSON: (VO): The difference in JOE: is startling.

JOE: The perspective from this side is just so much different than the other side. I mean, it’s incredible. Right now, I’m looking at, you know, just going forward instead of swimming against the tide. It’s a wonderful feeling.

DR TIMOTHY JOHNSON: (VO): Dr Schiffer reports that 40 percent of his patients had no response to the goggles, and 30 percent had a mild to moderate response. However, another 30 percent of his patients report an intense response, overall about the same response reported with Prozac. But even for the positive responders, the glasses are still just a tool.

DR FREDRIC SCHIFFER: No one is going to be helped by just putting on a pair of glasses. They’re an adjunct for teaching the person how to communicate with themselves.

DR TIMOTHY JOHNSON: (VO): But many of his patients say the glasses are the medicine they need to keep their mature mind in focus.

JOE: has had special sunglasses made that are tinted so he can see clearly to his left, but not to his right. They look like regular sunglasses, except that by forcing him to activate his optimistic mind, they provide a very practical boost to his mental health.

JOE: It gives you hope. And you know, hope is, you know, obviously a very important thing. Because with hope, anything can happen, and it’s worked for me.

SAM DONALDSON If this therapy looks easy enough to try at home, Dr Schiffer says it is. And you don’t even need goggles to do it. Simply hold your hands in front of your eyes, as you saw in our story, covering one eye completely, the other halfway-so you’re looking out from the extreme left or the extreme right. If you feel more relaxed seeing from one side than from the other, then goggle therapy might be able to put you in touch with the bright side of your brain. We’ll be right back.

Fish Oil

AOL News
Oct. 21, 2002 — It may sound fishy, but researchers say taking a daily fish-oil supplement may boost the effectiveness — or even replace — antidepressants for treating depression in some people.

In a new study, people who added a daily dose of omega-3 fatty acids to their regular antidepressant treatment had significant improvement in symptoms, including anxiety, sleeping problems, sadness, decreased sexual desire, and suicidal tendencies.

Although there are many effective treatments for depression, most only work in a limited number of patients or have significant side effects that prompt users to stop taking them. That’s inspired researchers to look for new ways to treat the mental illness or increase the effectiveness of existing treatments.

Previous studies have suggested that depressed people have lower-than-normal levels of a fatty acid known as EPA (eicosapentaenoic acid), which plays an important role in maintaining normal brain function.

In this study, the researchers examined the effectiveness of adding various dosages of EPA supplement to normal drug therapy in 70 people with persistent depression that was not responding to standard antidepressants. The results appear in the October issue of the Archives of General Psychiatry.

Researcher Malcolm Peet, MD, of Swallownest Court Hospital in Sheffield, England, and colleagues found that patients who took the lowest, 1-gram daily, fish-oil dose showed significant improvements on all major measures of depression compared with those who took a placebo. In particular, 69% of the patients who took the 1-gram dose had a 50% reduction in their symptoms, compared with only 25% of those who took a placebo.

A 2-gram dose showed little effect, but those taking the highest, 4-gram, dose showed a trend toward improvement in symptoms. The researchers say larger studies are needed to confirm these effects.

The omega-3 fatty acid may work to ease depression by improving the effectiveness and absorption of existing medications, the researchers say. But they note that a limited number of their patients who are not on antidepressant therapy have seen improvements similar to those seen in this study through treatment with fish-oil supplements alone.

In addition, they say treatment with omega-3 fatty acid may be especially beneficial for depressed patients who are at risk for heart disease, in light of recent research about fish oil’s heart-healthy effects.

Omega 3 Fatty Acids in Bipolar Disorder

Arch Gen Psychiatry. 1999;56:407-412

A Preliminary Double-blind, Placebo-Controlled Trial

Andrew L. Stoll, MD; W. Emanuel Severus, MD, PhD; Marlene P. Freeman, MD; Stephanie Rueter; Holly A. Zboyan; Eli Diamond; Kimberly K. Cress, MD; Lauren B. Marangell, MD

Background: 3 Fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate, 2 effective treatments for bipolar disorder. The present study was performed to examine whether 3 fatty acids also exhibit mood-stabilizing properties in bipolar disorder.

Methods: A 4-month, double-blind, placebo-controlled study, comparing 3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder.

Results: A Kaplan-Meier survival analysis of the cohort found that the 3 fatty acid patient group had a significantly longer period of remission than the placebo group (P=.002; Mantel-Cox). In addition, for nearly every other outcome measure, the 3 fatty acid group performed better than the placebo group. Conclusion 3 Fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder.

BIPOLAR DISORDER (manic-depressive illness) is a common neuropsychiatric illness with a high morbidity and mortality.1 Despite available mood-stabilizing drugs, such as lithium carbonate and valproate, the illness is characterized by high rates of recurrence.1, 2 Recent research suggests that all of the currently available mood-stabilizing drugs have inhibitory effects on neuronal signal transduction systems. These findings have led to the hypothesis that overactive cell-signaling pathways may be involved in the pathophysiological mechanisms underlying bipolar disorder.3-6 By using this model of mood stabilizer action based on suppression of neuronal signal transduction mechanisms, novel mood-stabilizing agents can be rationally developed. One promising group of compounds is the 3 fatty acids, obtained from marine or plant sources.7 Among other effects, the ingestion of large amounts of 3 fatty acids is associated with a general dampening of signal transduction pathways associated with phosphatidylinositol, arachidonic acid, and other systems.8, 9 Thus, 3 fatty acids may be useful in conditions such as bipolar disorder, where the pathophysiological process may involve overactivity of cell signal transduction.

We hypothesized that orally administered 3 fatty acids would exhibit inhibitory effects on signal transduction mechanisms in human neuronal membranes, and that high-dose 3 fatty acids would be an effective mood stabilizer in bipolar disorder. The goal of this preliminary study was to assess the subacute mood-stabilizing effects of 3 fatty acids in patients with unstable bipolar disorder.

PATIENTS AND METHODS

OVERVIEW

This was a 4-month, parallel-group, placebo-controlled, double-blind pilot study in which outpatients with bipolar disorder were randomized to receive either 3 fatty acids or placebo, in addition to their ongoing usual treatment.

PATIENTS

Participating subjects were men and women, 18 to 65 years old, who met DSM-IV10 criteria for bipolar disorder (types I or II), and were free of notable medical and psychiatric comorbidity. The diagnosis of bipolar disorder was established by means of all available clinical information, including the mood disorder module of the Structured Clinical Interview for DSM-IV.11 Patients were required to have had at least 1 manic or hypomanic episode within the past year, because the expected high risk of recurrence in this subgroup1 enhanced the power of the study to detect a difference between the 2 treatment groups within the study period. Forty percent of the study cohort had rapid-cycling symptoms, defined as 4 or more mood episodes in the 1 year before enrollment in the study.12 Patients were permitted to continue with their outpatient psychiatrist or psychotherapist, but no new psychotherapy treatment was started. Subjects receiving other medications at study entry continued to receive these medications at constant dosages, whether or not they were in the therapeutic range.

Table 1 summarizes the demographic and clinical characteristics of the study subjects. This study was approved by the human studies committees of Brigham and Women’s Hospital, Boston, Mass, and Baylor College of Medicine, Houston, Tex, and all participating patients gave written informed consent after receiving a full explanation of the study.

STUDY PROCEDURES

During the baseline visit, a detailed psychiatric and medical history was obtained, and the following standard rating scales were performed: Structured Clinical Interview for DSM-IV screening questions for current mania and depression, Young Mania Rating Scale13 (11-item structured interview version), Hamilton Rating Scale for Depression14 (31-item structured interview version), investigator- and patient-rated Clinical Global Impression scale,15 the Global Assessment Scale,10 and a brief adverse-effect rating scale. The rating scales were repeated during office visits at weeks 2, 4, 6, 8, 12, and 16. Because of a presumed delay in the therapeutic effects of 3 fatty acids, a priori criteria mandated that subjects remain in the study for 30 days or more to be included in the analysis. Identical gelatin capsules containing concentrated 3 fatty acid ethyl esters or placebo (olive oil ethyl esters) were obtained from the Fish Oil Test Materials Program, a joint research program of the National Institutes of Health and the National Marine Fisheries Service. Each capsule of 3 fatty acid concentrate contained 440 mg of eicosapentanoic acid (C20:5,3) and 240 mg of docosahexanoic acid (C22:6,3), which was vacuum deodorized and supplemented with tertiary-butylhydroquinone, 0.2 mg/g, and tocopherols, 2 mg/g, as antioxidants. The source of the 3 fatty acids was menhaden fish body oil concentrate.

Subjects were randomized by the Brigham and Women’s Hospital Research Pharmacy to receive either 3 fatty acid treatment or placebo. The randomization was stratified according to sex, the presence or absence of concurrent lithium treatment, and the presence or absence of rapid cycling. Subjects received 7 capsules twice daily, for a total daily 3 fatty acid dosage of 6.2 g of eicosapentanoic acid and 3.4 g of docosahexanoic acid. Patients randomized to placebo also received 7 identical capsules twice daily. A relatively high dosage of eicosapentanoic acid and docosahexanoic acid was used, because similar doses have been safely and effectively administered in other disease states. Furthermore, because of the lack of data regarding the effective dosage of 3 fatty acids in mood disorders, a relatively high dosage was chosen to avoid a potentially ineffective low dose. Blood levels of 3 fatty acids were not monitored in this trial.

OUTCOME MEASURES

The main outcome measure chosen a priori was the duration of time to exit double-blind treatment because of symptoms of bipolar disorder of sufficient severity to warrant a change in medication. Specifically, patients ended their participation in the study and treatment was considered to have change in medication. Specifically, patients ended their participation in the study and treatment was considered to have failed if mood symptoms emerged, or continued beyond 30 days in patients who were not euthymic at baseline. Hence, duration of time in the study represented an overall measure of treatment efficacy. The two blinded principal investigators (A.L.S. and L.B.M.), in collaboration with each patient, were responsible for the decision whether to end a patient’s participation in the study. Secondary outcome measures were the results of the Young Mania Rating Scale, Hamilton Rating Scale for Depression, Clinical Global Impression, and Global Assessment Scale ratings, before and after treatment.

STATISTICAL ANALYSIS

A power calculation was performed before the study to determine the appropriate sample size. Assuming a large effect size, we calculated that 60 patients (including dropouts) would be sufficient to demonstrate a difference between the 2 arms at 90% power with an .05.

The study was originally intended to include 60 randomized patients, each for 9 months of double-blind treatment. However, an unexpected cessation of production by the National Marine Fisheries Fish Oil Program led to a shortage of material. Simultaneously, a preplanned, blinded, interim analysis performed when 20 subjects had either failed treatment or completed 4 months suggested significant differences between the groups. The combination of these 2 factors led us to end accrual and then reanalyze the data after 30 patients had either failed treatment or completed at least 4 months of follow-up. A standard sequential design would prescribe looking for a P value of .02 or less to signal significance on the first interim analysis, and a P value of .04 or less to signal significance on the final analysis. Because of the 2 factors cited above, the results in this study fall between the interim and final analysis, and the P value designating significance could be taken conservatively as .015 or liberally as .042. A Kaplan-Meier “survival” analysis (Mantel-Cox log-rank statistic; df=1) was used to compare the duration of remission in the 2 groups. The rating scale scores on the last day of the study for each patient were used as the “final” data points (last observation carried forward). Categorical variables were analyzed by means of the Fisher exact test. Continuous variables were examined with the nonparametric Mann-Whitney test. Statistical significance for the primary outcome measure was set at Forty-four patients were randomized, but only 30 had evaluable data, based on the a priori criteria for inclusion. Four subjects dropped out before the 1 month point because of noncompliance with the study protocol (n=2), gastrointestinal tract side effects (n=1), or concern over the possibility of receiving placebo (n=1). The remaining 10 subjects had not yet reached the 4-month end point required for the main outcome measure when the trial was ended and therefore were not included in the analysis.

RESULTS

The results for the 30 patients with evaluable data, as defined above, are presented herein. There were no significant differences in the demographic and baseline clinical characteristics of the 3 fatty acid and placebo groups (Table 1). Figure 1 depicts a Kaplan-Meier survival analysis of the study cohort. The duration of time remaining in the study was significantly greater in the 3 fatty acid?treated group when compared with placebo (P=.002; Mantel-Cox, log-rank statistic, 21=9.990). The time to a 50% rate of ending the study prematurely (“nonresponse”) was 65 days for the placebo group, reflecting the unstable nature of the study population. A post hoc analysis was also performed for the subgroup of 8 subjects who entered the study while receiving no other mood-stabilizing drugs. As was observed in the whole study cohort, the 4 subjects who received 3 monotherapy remained in remission for a significantly longer time than the 4 subjects who received placebo monotherapy (Figure 2; P=.04; Mantel-Cox). Other post hoc analyses showed that sex, the presence or absence of rapid cycling, and the type of bipolar disorder (I vs II) did not predict response to 3 fatty acids, although the number of subjects in each cell was small.

Table 1 displays the comparison of the secondary outcome measures between the 3 and placebo groups. For nearly every outcome measure, the 3 fatty acid group performed better than the placebo group.

Three patients developed side effects of the study drug and were permitted to lower the dosage to a minimum of 5 capsules twice daily. The most common adverse effect in both the 3 and olive oil groups was mild gastrointestinal tract distress, generally characterized by loose stools. Of the patients with adverse effect data at week 4 of the trial, 8 (62%) of 13 3-treated subjects complained of mild gastrointestinal tract side effects, whereas 8 (53%) of 15 placebo-treated subjects experienced gastrointestinal tract side effects (P=.72 by Fisher exact test; 2 subjects with missing data). No other adverse effects appeared with significant frequency or severity, and overall the patients tolerated the trial well. No research subjects were hospitalized or developed marked suicidal ideation or behavior. Demographic and clinical data for each subject are listed in Table 2.

COMMENT

3 Fatty acids used as an adjunctive treatment in bipolar disorder resulted in significant symptom reduction and a better outcome when compared with placebo in this pilot study. Improvement was significantly greater in the 3 fatty acid group than the olive oil control group on almost every assessment measure. The striking difference in relapse rates and response appeared to be highly clinically significant.

These pilot results are intriguing and suggest that the addition of 3 fatty acids improved the subacute course of illness in this cohort of patients with bipolar disorder. The baseline clinical state of the research subjects in this study did not permit an evaluation of the antimanic effects of 3 fatty acids. Although the study was also not designed to provide definitive data on antidepressant effects, most of the patients receiving placebo who were considered treatment failures exhibited depressive exacerbations or recurrence. The suggestion of antidepressant effects of 3 fatty acids in this cohort of patients is noteworthy and warrants further study.

Although this was a double-blind, placebo-controlled study, several methodological factors must be considered. The mixture of bipolar types I and II, varied mood states at study entry, and varying concomitant medications was a less rigorous design than in the ideal clinical trial. The variability in the clinical profiles of the study patients was controlled to some degree by stratifying the randomization for sex, concurrent lithium treatment, and rapid cycling. It would be ideal, although impossible in a small study, also to stratify for other variables. However, the randomization did result in a comparable representation of key variables in the active and control groups, including concomitant medications and baseline mood state.

A further concern is the potential compromise of the blind. A distinct “fishy” aftertaste was episodically reported by subjects in both groups, but more often in the 3 group. When patients were asked to guess their randomization status, 86% of the 3 group guessed correctly, compared with 63% of the placebo group. Although in some cases the guess was based on the presence of a fishy aftertaste, in many cases it was based on the patient’s perceived clinical response (or lack thereof in the placebo group). Correctly guessing a putative active treatment in the presence of a good clinical response is probably unavoidable. However, the possibility that the 3 group exhibited a placebo effect must be considered. Future studies to replicate and extend these findings should consider strategies to improve the blind, such as using a lower dose of 3 fatty acids to reduce the frequency of the fishy aftertaste, or alternatively adding a small amount of a fishy-tasting substance to the placebo.

If the results of this study are correct, and 3 fatty acids do possess mood-stabilizing action, then there are tangible implications for our understanding of the pathophysiological mechanisms of bipolar disorder and for the development of future treatments. Biochemical studies of human white blood cells show that high-dose therapy with 3 fatty acids leads to the incorporation of these polyunsaturated compounds into the membrane phospholipids crucial for cell signaling.8, 16 Increased concentrations of 3 fatty acids in membrane phospholipids appears to suppress phosphatidylinositol-associated signal transduction pathways.8, 16 The precise mechanism of this effect remains unclear. However, the incorporation of the polyunsaturated 3 fatty acids into the lipid bilayer of the cell membrane alters the physical and chemical properties of the membrane,17 possibly producing a local environment in which the membrane phospholipids are more resistant to hydrolysis by phospholipases. This could result in reduced generation of the second messenger molecules diacylglycerol and inositol triphosphate, thereby producing less activation of “downstream” intracellular signaling molecules, such as protein kinase C and calcium ion (Figure 3).

As in peripheral tissues, the 3 fatty acids are also highly incorporated into neuronal phospholipids in animal models.18 Thus, it is possible that the 3 fatty acids also inhibit signal transduction mechanisms in the human central nervous system. Recent work by several investigators3-6 strongly suggests that the mechanism of action of typical mood stabilizers, such as lithium and valproate, involves a similar inhibition of postsynaptic signal transduction processes (Figure 3). Our results support other data suggesting that the mechanism of action of mood stabilizers in bipolar disorder is the suppression of aberrant signal transduction pathways. This is consistent with a model of abnormal signal transduction as the pathophysiological basis of bipolar disorder. If further studies confirm their efficacy in bipolar disorder, 3 fatty acids may represent a new class of membrane-active psychotropic compounds, and may herald the advent of a new class of rationally designed mood-stabilizing drugs.

REFERENCES

1. Goodwin FK, Jamison KR. Manic Depressive Illness. Oxford, England: Oxford University Press; 1990.

2. Gitlin MJ, Swendsen J, Heller TL, Hammen C. Relapse and impairment in bipolar disorder. Am J Psychiatry. 1995;152:1635-1640.

3. Stoll AL, Severus E. Mood stabilizers: shared mechanisms of action at post-synaptic signal transduction and kindling processes. Harvard Rev Psychiatry. 1996;4:77-89.

4. Berridge MJ, Downes CP, Hanley MR. Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem J. 1982;206:587-595.

5. Chen G, Manji HK, Hawver DB, Wright CB, Potter WZ. Chronic sodium valproate selectively decreases protein kinase C a and e in vitro. J Neurochem. 1994;63:2361-2364.

6. Manji HK, Bersudsky Y, Chen G, Belmaker RH, Potter WZ. Modulation of protein kinase C isozymes and substrates by lithium: the role of myo-inositol. Neuropsychopharmacology. 1996;15:370-381.

7. Stensby ME. Nutritional properties of fish oils. World Rev Nutr Diet. 1969;11:46-105.

8. Sperling RI, Benincaso AI, Knoell CT, Larkin JK, Austen KF, Robinson DR. Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. J Clin Invest. 1993;91:651-660.

9. Tappia PS, Ladha S, Clark DC, Grimble RF. The influence of membrane fluidity, TNF receptor binding, cAMP production and GTPase activity on macrophage cytokine production in rats fed a variety of fat diets. Mol Cell Biochem. 1997;166:135-143.

10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994.

11. Spitzer R. Structured Clinical Interview for DSM-IV. Washington, DC: American Psychiatric Association; 1994.

12. Dunner DL, Fieve RR. Clinical factors in lithium carbonate prophylaxis failure. Arch Gen Psychiatry. 1974;30:229-233.

13. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429-435.

14. Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 1988;45:742-747.

15. Guy N. ECDEU Assessment Manual for Psychopharmacology. Washington, DC: US Dept of Health, Education, and Welfare; 1976.

16. Medini L, Colli S, Mosconi C, Tremoli E, Galli C. Diets rich in n-9, n-6 and n-3 fatty acids differentially affect the generation of inositol phosphates and of thromboxane by stimulated platelets, in the rabbit. Biochem Pharmacol. 1990;39:129-133.

17. Barton PG, Gunstone FD. Hydrocarbon chain packing and molecular motion in phospholipid bilayers formed from unsaturated lecithins. J Biol Chem. 1975;250:4470-4476.

18. Bourre JM, Bonneil M, Clement M, Dumont O, Durand G, Lafont H, Nalbone G, Piciotti M. Function of dietary polyunsaturated fatty acids in the nervous system. Prostaglandins Leukot Essent Fatty Acids. 1993;48:5-15. 1999 American Medical Association. All rights reserved.

Fish oil found to ease manic depression – US study

May 13
Reuters

The fatty oil found in salmon, cod and other fish, already touted for its effectiveness in combating heart disease and arthritis, may also alleviate the symptoms of manic depressives, researchers said on Thursday. In what experts described as a limited but landmark study of how a naturally occurring dietary ingredient can affect the brain, researchers found that patients suffering from manic depression given capsules containing fish oil experienced a marked improvement over a four-month period.

“The magnitude of the effects were very strong. Fish oil blocked the abnormal signalling (in the brain) which we think is present in mania and depression,” lead researcher Andrew Stoll, the director of the pharmacology research laboratory at Harvard University’s McLean Hospital, said in a telephone interview.

The study, published in the American Medical Association’s Archives of General Psychiatry, comprised 30 patients diagnosed with bipolar disorders, which are characterised by chronic bouts of mania and depression.

Roughly half the subjects received fish oil supplements and half got capsules containing olive oil, a placebo. They underwent psychological testing at two-week intervals during the four-month study.

The chemicals in the fish oil believed to be at work on the subjects’ brains were omega-3 fatty acids, which are present in certain types of fatty fish such as salmon and cod. They are also found in canola and flaxseed oil.

Among the many health benefits sometimes attributed to omega-3 fatty acids are smoothing blood flow through constricted arteries of heart disease patients, lubricating painful joints in rheumatoid arthritis sufferers, cutting women’s risk of breast cancer, preventing an intestinal inflammation known as Crohn’s disease, and even ridding the body of cellulite.

But there has been little done on the effect of omega-3 fatty acids on the human brain.

Stoll said omega-3 fatty acids boost levels of the neurotransmitter serotonin in the brain — similar to the effect of popular anti-depressants such as Prozac — although the mechanism by which either works remain uncertain.

He said previous research on animals showed that omega-3 fatty acids replenished the “lipid bilayer” surrounding the body’s cells, including brain cells, where receptors reside that receive signals from chemical transmitters.

Stoll theorised that diets in Western industrialised countries are low in fish and other foods containing omega-3 fatty acids, a deficiency that can be compensated for by consuming fish oil or flaxseed oil supplements.

Patients in the study received up to seven capsules daily with concentrated fish oil from menhaden, a type of Atlantic herring, containing a total of nearly 10 grams of fatty acids.

“If you’re treating depression and bipolar disorder, you have to think of it as a medicine and take an adequate amount,” Stoll said. He suggested that omega-3 fatty acids might be taken as an adjunct to anti-depressant drugs or lithium, which is commonly prescribed to treat bipolar disorders.

In a commentary on the study that was published in the journal, three researchers from Case Western Reserve University said it had “substantial limitations” partly because of its small size, but called it “a landmark attempt.”

“Methodology aside, the fact remains that this is, I think, a critical study looking at the role of agents which are naturally occurring substances that are well tolerated — patients nowadays have a high affinity for taking the most effective, least toxic agent they can find,” Dr. Francisco Fernandez, chairman of the department of psychiatry at Loyola University Medical Centre, told Reuters.

“It suggests that these agents may be effective in bipolar disorders, maybe equivalent to psychotropic agents,” he said, describing the effect of the omega-3 fatty acids as setting off a “cascade of chemicals’ ‘ that aid cell functioning.

The drawback is that no drug company was likely to throw its resources behind studies of fish oil, because it cannot be patented and profited from. Fernandez and the other researchers suggested government-financed research.

FATS FOR MENTAL HEALTH

Saturday Evening Post
Cory SerVaas, Patrick Perry
03-01-1999

New scientific studies suggest that by increasing our consumption of certain “good” fats found in fish, flaxseed oil, and walnuts, we may improve the symptoms of a number of psychiatric illnesses, including depression, bipolar disorder, and schizophrenia. For years, investigators have been exploring the link between depression and diet, especially the association between the incidence of depression and fish consumption. Fish and some land-based foods are rich in omega-3-a nutritional building block critical for the healthy development and functioning of the brain and nervous system.

In the past 100 years, the American diet has shifted away from the diet of our human ancestors-wild plants and game, including fish-which was rich in omega-3 fatty acids to one relying on mass-produced and highly processed food. By reducing our consumption of omega-3s in favor of another fat called omega-6 fatty acid, found in vegetable oils such as corn and soy, we have upset a delicate balance that may underlie the increasing rate of depression and other chronic diseases in contemporary American society. In cross-national studies comparing diet, scientists found that in countries where fish is still a large part of the diet, such as in Taiwan and Japan, rates of depression were lower than in American and many European populations.

We spoke with Joseph R. Hibbeln, M.D., about this emerging field of scientific research. Dr. Hibbeln is an internationally recognized authority on the link between essential fatty acids and depression. Chief of the Outpatient Clinic, Laboratory of Clinical Studies at the National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health in Bethesda, Maryland, Dr. Hibbeln co-organized the first “NIH Workshop on Omega-3 Essential Fatty Acids and Psychiatric Disorders,” held last September.

Q: In layman’s terms, what are omega-3 fatty acids?

A: Omega-3 refers to a class of polyunsaturated fatty acids that are beneficial to many aspects of health. Polyunsaturated fatty acids are all essential fatty acids in that they must be derived from the diet-they can’t be manufactured by the body. Among polyunsaturated fatty acids, there are two classes or families-an omega-6 and an omega- 3.

Balance between these two families is very important to proper human functioning and well-being.

The two families are not interchangeable. For example, if you eat foods high in omega-6 fatty acids, your body composition will change over to have lots of omega-6 fatty acids. If you eat foods high in omega-3 fatty acids, your body tissues will eventually develop a higher proportion of omega-3 fatty acids.

Q: Why are omega-3s so important?

A: Of the omega-3 fatty acids, two are especially biologically important-one is EPA, eicosapentaenoic acid, and the other is DHA, decosahexaenoic acid. In a nutshell, DHA is very biologically important because it is highly concentrated in the brain-in the synapses, where brain cells communicate with one another. And DHA is one of the important fats that make up the wall of the cell.

To illustrate this point, if you are building a house and pouring concrete, DHA would be what the concrete is made of-it is literally the wall of the cell. Depending on what kind of fatty acids you put into that cell wall, the wall or membrane will possess different physical properties. If you make the foundation out of saggy concrete, it will affect many different systems in the house-windows, electrical systems, etc. In a similar manner, the type of fatty acids that you eat will eventually create the cells of your membranes and therefore affect how they function. That is one reason why DHA is important.

Q: What role does the other omega-3 fatty acid – EPA – play in our health?

A: EPA becomes a very potent, biologically active molecule that keeps platelets from coagulating or clotting. When EPA gets into white blood cells, it helps reduce inflammation and immune responses. EPA affects the body in many other ways-sleep patterns, hormones, etc.-serving as a modulator.

Q: What function do omega-6s have in the body?

A: One omega-6 fatty acid, arachodonic acid (AHA), makes biological compounds which have the opposite effect from the compounds made from EPA. For example, if you have a platelet with a lot of arachodonic acid in its cell wall, it will clot more easily and you are therefore more likely to clot off a blood vessel during a stroke. If the platelet has EPA in its cell wall, it is less likely to clot.

Once again, the important factor here is achieving a balance between these two families-the omega-3s and the omega-6s.

Q: So people need both omega-3 and omega-6, but in what proportion?

A: Proportion is a critical question. One way to answer the question is to study human evolution and look at the diet human beings evolved on. It’s quite clear that even if you don’t account for fish in the diet, the ratio of omega-6s to omega-3s in our paleolithic diet was about one-to-one. During our evolution, we ate a variety of different plant sources and leafy green vegetables, nuts, and free-range animals that ate leafy green vegetables: wild game has about a one-to-one ratio of omega-6 to omega-3.

Q: How has our diet changed?

A: In the past 100 years, the balance of omega-6s to omega-3s has radically changed from the diet we evolved on and what, it could be argued, we are optimally suited for. We now grow seed oils, such as corn and soybeans, in great abundance. As seed oils, they have much higher ratios of omega-6s to omega-3s. Corn oil, for example, has a ratio of about 74 or 75 omega-6s to one omega-3.

Q: Flaxseed is a seed, but it contains more omega-3, right?

A: Yes, flaxseed is an exception.

DEPRESSION

Q: Tell us about your current research findings on depression. Is depression less common in countries where they consume more omega- 3 fatty acids?

A: In April 1998, I published a paper in Lancet in which I compared the annual prevalence of depression across countries to a measure of their fish intake. I took the data points from a paper, published in the Journal of the American Medical Association by Myrna Weissman, M.D.-an epidemiologist at Yale University who is recognized as the world’s expert in psychiatric epidemiology; the quality of the epidemiological data is really the gold standard.

The country with the lowest prevalence of depression was Japan at about 0.12, and the highest was New Zealand at almost 6 percent. The paper describes nearly a 60-fold difference in the prevalence of depression-not double or times five-but a 60-fold difference. Virtually all of the differences across those countries appeared to be predicted by how much fish people were eating.

Q: Has the prevalence of depression changed over the past century?

A: I mentioned the differences in incidence of depression across countries, but another way of testing the hypothesis that depression is related to our dietary intake of omega-3s is to look at differences in depression across time, especially in the past century. Long before I began this work, psychiatrists noted, and described very well, that the prevalence of depression has been on a marked increase in the past century depending on what birth cohort you were born in. You are about 100-fold less likely to be depressed by the age of 35 if you were born before 1914, than becoming depressed by the age of 35 if you were born after 1945.

As I mentioned to you, 100 years ago we were eating much closer to our paleolithic diet, because the world was still a much more rural community. We didn’t yet have mass agricultural production of corn and soybeans or hydrogenation. My parents still remember when they were eating only butter, which has few omega-6s, instead of margarine.

Q: Have studies demonstrated how depression is affected by fish consumption?

A: I have, for example, done an epidemiological comparison with postpartum depression, although the study is as yet unpublished. It appears that countries where more fish is consumed have much lower rates of postpartum depression. The finding makes sense, because mothers deplete themselves of omega-3 fatty acids while supplying them to the developing infant, presumably for their neuronal development. During gestation and lactation-it is well known-women can become depleted of omega-3 fatty acids. It can take up to 36 months for women to return to their normal levels, so depleted levels of omega-3 fatty acids may very well be one of the factors contributing to postpartum depression. The prevalence of postpartum depression is also much lower in countries where more fish is consumed.

Q: Can omega-3 supplementation help relieve the depression?

A: At the NIH workshop last September, data was presented from a study done by Dr. Antolin Llorente, Ph.D., at Baylor University, where women were given DHA during pregnancy. The study was originally devised to be a biochemical study; it wasn’t really designed to study depression or moods. They did, however, recruit depressed women. The women in the study were basically very healthy, normal, upper-class, well-nourished women. Nonetheless, they found that those women receiving the DHA supplements had better measures of attention and concentration than women receiving placebos.

Q: How much DHA were they given?

A: They were given about 200 mg per day of DHA. It was a double-blind, placebo-controlled study in capsules versus a placebo oil.

Q: We’ve recently read that there is a link between depression and cardiovascular disease. Are the two connected?

A: My data relating countries and their fish consumption, published in the Lancet, suggest that fish consumption protects against depression and cardiovascular disease.

Second, psychologists have known for a long time that there is a link between either depression and/or hostility and cardiovascular disease. If you have one, you are more likely to have the other.

For many years, people have asked the question: Does depression cause cardiovascular disease, or does cardiovascular disease cause depression? What I put forth as a hypothesis is that depression and cardiovascular disease are both manifestations of a common nutritional deficiency.

Depressed patients have been shown to have higher cardiac risk factors from their diets and are, for example, more likely to die of arrhythmias, excessive platelet clotting, or to have elevated cytokines-an immune reaction. All of these conditions parallel what could happen in people with low levels of omega-3 fatty acids.

Most of the work that I have done, and described to you, has largely been theoretical and hypothesis-building. But since that hypothesis, there are five published studies showing that depressed patients have lower levels of omega-3 fatty acids than do control subjects.

Q: Do studies suggest that increasing consumption of omega-3 fatty acids-through diet or supplementation-could have a positive effect for patients with depression?

A: Yes. Some chemistry data also suggest it, as do data among suicide patients and data on hostility and violence. That aside, it took me a while to really come to this opinion. During a conversation with a person at one of the nutritional journals, the interviewer asked, “What’s the harm of a depressed patient taking three grams of omega- 3s per day?” Well, there is no harm that we know of. There’s no risk and a possible benefit. In other words, it can’t hurt and it might help.

Q: How are omega-3 levels measured?

A: Omega-3 levels are measured by analyzing plasma or red blood cells. The test will indicate what concentrations of omega-3 fatty acids are in your blood.

Q: Is the test expensive?

A: It is about a $100 or $150 lab test.

Q: Is the test widely available?

A: No. It is largely a research test at this point. Johns Hopkins’ Kennedy Kreger Institute, for example, can do it reliably. The trouble with getting your plasma drawn right now is that while we can analyze the level, we don’t know what level is optimal for depressed patients as yet. If you take what is normal for the United States right now in the latter half of the 20th century, I can’t tell you if that level is optimal.

BIPOLAR DISORDER

Q: Are omega-3s helpful for patients with manic-depression or bipolar disorder?

A: The most exciting and best clinical data from double-blind, placebo- controlled treatment trials is in schizophrenia and manic depression.

In manic depression, the treatments of choice with the best record of efficacy are lithium, valproic acid, and carbamazapine. The action of these drugs in these conditions is well known, and they are still the treatments of choice.

Q: But do higher serum levels of omega-3 play a role in efficacy of these treatments for bipolar disorder?

A: Andrew Stoll, M.D., at Harvard did a double-blind, placebo-controlled trial in bipolar disease. In the study, patients had recently been hospitalized and had either a severe mania or severe depression. All the patients were on medications-lithium and valproic acid. One half of the patients were assigned to take six grams of omega-3 fatty acids a day; the other half were assigned to placebos. After four months, researchers did a preliminary review of the data, and the ethics committee made them stop the trial and put everybody on the active agent, because only one out of 16 of the people taking the omega-3s relapsed into a mania or depression, whereas 8 or 9 out of 15 relapsed on the placebo.

Q: Is six grams a very large dose?

A: Yes, but Eskimos ate diets that were almost completely omega-3 fatty acids, and they had low rates of heart diseases and arthritis.

Q: Is depression common among Eskimos?

A: We don’t know. I have looked for that data. But by the time people were doing epidemiological studies of Eskimos, they were eating Western diets.

Q: Is there a toxic level of omega-3?

A: The FDA recognizes up to 3 grams per day of omega-3s as GRAS, or Generally Recognized As Safe.

Q: What are the side effects if you consume more than three grams?

A: It will definitely have a greater effect in thinning your blood and making your platelets not coagulate.

Q: If you had a hemorrhagic stroke, you would be in trouble.

A: Right. That’s why Japanese people die more frequently of hemorrhagic stroke, but have lower death rates overall.

Q: And lower rates of depression?

A: Right. And apparently also lower hostility and violence.

Q: That finding is very interesting, especially for countries where there is more hostility and violence.

A: One very reasonable question people ask me is, “Isn’t it possible that it’s just the Japanese culture that is different and less hostile?” I say, “Well, Japan has approximately onehalf the population of the United States living on an arable land mass the size of Connecticut. And it’s a stressful society. Just on the basis of crowding, you would expect higher rates of depression and hostility.”

One thing also to consider about the culture is what would happen to a culture, or group of people, if you gave them a psychotropic drug that made them calmer for a couple hundred years. It’s quite possible that these brain-specific nutrients have had an effect on culture over a long period of time.

Q: We have interviewed researcher and author Kay Redfield Jamison, M.D., who is manic-depressive. She is at Johns Hopkins and would probably be very interested in your work.

A: Some of my data were recently presented to a National Institutes of Mental Health group. Apparently, Kay was there, or heard about it. I have data of EPA levels in suicide attempters. It looks very much like the curve with depression, in that high plasma levels of EPA predict much lower psychological risk factors toward suicide. Dr. Jamison is doing work on suicide right now, so she called me up and we had a long talk. I sent her information. She actually just sent me a copy of her book, so I have had contact with her.

Q: What is rapid-cycling bipolar disease, and is it common?

A: Rapid cycling is anything more frequent than four times per year, but it can be as frequent as every other day or minute-to-minute in some cases. It is not common and very difficult to treat, often treatment-resistant.

Q: In rapid cycling every other day, for example, it is hard to understand how omega-3s could be a factor. If the tissues are deficient in omega- 3s, how would that trigger the depression, then euphoria, every other day?

A: The brain works in a series of interlinked neural networks, trained to cycles of biological rhythms. What occurs in patients with rapid- cycling bipolar disease is that the brake-the modulator of cycles-is gone. Although not well-defined biochemically, the theory is that omega-3s help put back a brake on that cycling or disrupted, endogenous biological rhythm. In no way are omega-3s proven to be effective in rapid-cycling bipolar disorder. All we have are anecdotal reports in rapid-cycling disorder at this point.

Q: What about the influence of omega-3s in schizophrenia?

A: Malcolm Peet, M.D., in England has given omega-3 fatty acids to patients suffering from schizophrenia. He found a good effect in reducing psychosis and negative symptoms, such as diminished social function. Omega-3s improved their social functioning. It has shown very good effect in this regard.

Q: Can it help people with attention deficit hyperactivity disorder (ADHD)?

A: There has been a lot of discussion about using omega-3 fatty acids in attention deficit hyperactivity disorder. At the NIH conference, everybody who has done a clinical study was present. Two of the three studies discussed showed no effect. The third study showed a good effect, using a combination of omega-3s and omega-6s. What was troubling about this study was that they also sell the product that they investigated.

At this point, there is no strong, compelling double-blind data that shows omega-3s are effective for people with ADHD. Scientific data aside, however, I have heard some impressive stories of efficacy from parents in anecdotal reports. The jury is still out on ADHD.

Q: It would seem that if a parent had a schizophrenic child or a child with ADHD, it wouldn’t hurt to give omega-3s.

A: Right, it won’t hurt and it might help.

SOURCES OF OMEGA-3

Q: Do you think people in the United States need to be concerned about getting more omega-3s into their diet?

A: Yes. A very good description of the whole omega-3 phenomenon is in a book called The Omega Plan by Artemis P. Simopoulos, M.D., and Jo Robinson. I don’t endorse the book, but I think it is a good layman’ s literature and reference. Your readers would probably appreciate it.

Dr. Simopoulos bases much of her work on the Crete diet and study. In the seven-country Crete study, men from the Greek island of Crete had the longest lifespans and lowest incidence of cardiovascular disease of men studied. [The six other countries in the study were Italy, the Netherlands, Finland, Yugoslavia, Japan, and the United States.]

The Crete men basically achieved this state of health and longevity by consuming fish, or foods that contain omega-3s, with almost every meal. Secondarily, they used olive oil for their salad dressings, instead of corn oil or soybean oil, as we do in the typical American diet, in which vegetable-oil-based salad dressings and margarines are rich sources of omega-6s.

Q: If fish are farm-fed using corn, would the fish then contain higher levels of omega-6s?

A: That’s quite right. Fish farmers have realized that if they just feed their fish with corn and soybeans, the fish don’t grow as well and don’t reproduce. Fish farmers now give a minimum amount of fish protein by farming menhaden-a source of fish protein-from the ocean. Apparently, the menhaden provides just enough omega-3s so that the farm-raised fish will reproduce.

Q: What about ersatz, or imitation, fish sold in the fish market as sea legs?

A: Almost any seafood, even if farmed, will probably have more omega- 3 fatty acids in it than will, for example, hamburger meat. Of course, wild seafood will probably have more omega-3s than farmed seafood, but you almost have to analyze omega-3 content on a case-by-case basis.

Overall, you are better off getting omega-3s from seafood.

Q: Are there manufacturers of fish-oil products who are superior to others? Are there products that our readers should look out for?

A: The general rule of thumb is that if you cut the capsule open and it smells like rotten, spoiled fish, it is spoiled fish. When you buy fish from the store and it is fresh, it doesn’t smell fishy. I don’t feel that I should pick on anybody in particular.

I will tell you that a good, common concentration in a one gram capsule would be 300 mg of EPA and 200 mg of DHA per gram. That’s pretty good. That concentration gives 0.5 g omega-3 fatty acids per gram tablet. It makes it pretty easy to calculate. If you take two capsules, you are getting one gram of omega 3s. If you take four of them, you get two grams. With six, you get three grams, etc.

Q: In our grandparents’ day, parents gave their children cod liver oil.

A: Yes, but they didn’t give six grams. I want to mention that people should not consume large amounts of cod liver oil in order to get omega-3s into their diet. Cod liver oil also contains a lot of vitamin A. If you were going to get three grams of omega-3s from cod liver oil, you would quickly reach toxic levels of vitamin A, so avoid cod liver oil.

Q: Do fish oil supplements provide the same benefits?

A: Your body pretty much doesn’t know whether you are getting it from fresh fish or a fish oil supplement.

Q: What about canola oil?

A: Canola oil is better; it has a better ratio of omega-6s to omega- 3s-around five or seven omega-6s to one omega-3.

Q: Is flaxseed oil the best source of omega-3?

A: Right, of the direct oil sources.

Q: What about nuts, such as walnuts?

A: Walnuts are good. I haven’t looked at the data carefully. But nuts, in general, are a pretty good bet. If you go with the principles of the paleolithic diet, it’s clear that we were eating a lot more fruits and nuts than wild game.

Q: How much omega-3 do you take?

A: I take about one gram per day and eat a lot of different types of fish.

Q: Deep-sea fish, not farm-fed catfish?

A: Farm-fed catfish are going to have less omega-3s, but they are going to have some.

Q: What is your next research project?

A: I am looking at whether consuming these omega-3 fatty acids reduces hostility and aggression. We looked at 235 subjects on whom we have performed lumbar punctures and taken cerebrospinal fluid for analysis. One of the markers of brain neurochemistry in the cerebrospinal fluid is a metabolite, or breakdown, of serotonin called 5HIAA. It is well known in biological psychiatry that people who have low concentrations of this 5HIAA are especially prone to suicidal and impulsive behaviors. What I found among normal subjects was that low concentrations of DHA in the plasma correlated to low concentrations of 5HIAA in their cerebrospinal fluid. This finding is important because 5HIAA predicts serotonin levels, and serotonin is really key to the biochemistry of depression and the biochemistry of suicide and violence.

Q: Serotonin levels should be high, right?

A: Right.

Q: Do you have access to prison inmates who have been given spinal- fluid taps from which you could determine whether the impulsive, violent person is low in omega-3s?

A: We are engaged in that work right now. We are taking cerebrospinal fluid samples before and after giving them either the omega-3s or placebos.

ADDED MATERIAL

Cory SerVaas, M.D., & Patrick Perry

Walnuts are especially good for their omega-3 content.

Flaxseed for salads and baking.

“The research being conducted is fascinating and potentially very important to the understanding and treatment of bipolar disorder,” commented Kay Redfield Jamison, M.D., of Johns Hopkins University on the role of omega-3 essential fatty acids and psychiatric illnesses. Dr. Jamison, who controls her manic-depressive illness, is a prominent researcher and has authored several books on the disorder.

An omega-3 fatty acid called DHA is highly concentrated in the synapses where brain cells communicate and plays a key role in brain development and function. A vast communications network within our brain is formed when chemical messengers, or neurotransmitters, are released from the axon, cross the synapse, and bind to receptors on another neuron.

New Self-Help Booklets Promote Recovery For People with Mental Illnesses

Techniques to help reduce the effects of trauma, make lifestyle changes to positively affect emotional well-being, and build strong relationships are a few of the issues addressed in a series of new self -help guides developed to help people with psychiatric disabilities. The booklets were released today by the Substance Abuse and Mental Health Services Administration (SAMHSA).

“The self-care skills and strategies outlined in the guides can be used to complement other mental health care treatment,” said SAMHSA Administrator Charles G. Curie. The guides offers practical steps that people need to keep in mind as they work on their own recovery.

The booklets, produced by SAMHSA’s Center for Mental Health Services, cover the following topics: Building Self-esteem, Making and Keeping Friends, Dealing with the Effects of Trauma, Developing A Recovery and Wellness Lifestyle, Speaking Out for Yourself, Action Planning for Prevention and Recovery.

The Recovering Your Mental Health series offers specific information guided by an understanding of consumer self-help issues, to enhance quality of life for people from a variety of backgrounds. There are six booklets in the comprehensive, yet brief series. Each booklet contains ideas and strategies that people from all over the country have found to be helpful in managing their own illnesses and services. A section on additional resources is located at the end of each guide.

“These user-friendly guides will help persons living with mental illness to achieve higher levels of wellness, stability and recovery,” says Bernard S. Arons, M.D., Director of the Center for Mental Health Services.

Copies of these six new self-help guides are available free of charge by calling SAMHSA’s Clearinghouse at 1-800-789-2647; TTY 301-443-9006 or logging on to http://www.samhsa.gov.

CMHS is a component of the Substance Abuse and Mental Health Services Administration (SAMHSA). SAMHSA, a public health agency within the U.S. Department of Health and Human Services, is the lead federal agency for improving the quality and availability of substance abuse prevention, addiction treatment and mental health services in the United States. Information on SAMHSA’s programs is available on the Internet at www.samhsa.gov.

Do Vitamins or Minerals (Apart From Lithium) Have Mood-Stabilizing Effects?

Charles W. Popper, M.D.
The Journal of Clinical Psychiatry
Dec 2001

Nutritional scientists have been well funded by agribusiness to find ways to deal with factors that interfere with animal health, including aggressive and destructive behavior. When farm animals become “violent”-when pigs start biting each others’ ears and tails, when chickens attack chickens-farmers have learned that the aggressive behavior can be reduced by adding certain minerals and vitamins to their diet, without the need for veterinary intervention.

In 1996, animal nutrition specialist David L. Hardy described this approach to Anthony F. Stephan, whose children had severe treatment-resistant bipolar disorder. Stephan then added similar nutrients to his children’s diet. On the nutritional supplements, both children stabilized clinically and have not needed psychiatric medication for the last 5 years. Hardy and Stephan began advising family members and friends about this nutrient supplement and have now worked with over 2500 psychiatric patients (D. L. Hardy, personal communication, 2001). They also began to collaborate with Bonnie J. Kaplan, Ph.D., a research psychologist at the University of Calgary in Alberta, Canada.

In this issue, Kaplan and colleagues (1) describe an open trial of the first 14 adults with bipolar disorder treated with this nutritional supplement, which consists of a broad range of minerals and vitamins, plus 3 amino acids and several antioxidants. Symptom reductions were clinically noted within 2 weeks and sustained over 6 months of observation. All outcome measures showed significant improvements (55% to 66% symptom reduction), and a strong effect size (> .80) was observed for ratings of depression as well as mania. Most patients could reduce their doses of psychiatric medications, and some patients became stable without any psychiatric medication. Only 2 patients started on new medications that might conceivably have contributed to their stabilization. Even allowing for the usual overestimation of effects in open-label series, these preliminary findings raise interesting questions about nutrition-behavior interactions.

In view of the 50 years of experience with lithium, the notion that minerals can treat bipolar disorder is unsurprising. However, the nutrient supplement studied by Kaplan and colleagues contains no lithium. Might other dietary nutrients have mood-stabilizer properties?

Some may object that a clinical trial of a mixture of ingredients is inherently unscientific: How can one know which ingredient is the active one, whether a smaller number of ingredients will have the same clinical effect, or whether the same ingredients are active in different patients? These questions will become worth pursuing once it has been formally determined whether the mixture, handed down from animal husbandry as a single entity, works in humans. Kaplan’s open-label report justifies her now ongoing controlled study, whose outcome appropriately precedes pursuing questions of mechanism of action (2) and parsimony.

Even so, it is difficult to avoid speculating about possible mechanisms. Might minerals serve as catalysts for enzymes involved in neurotransmitter metabolism, change drug biotransformation, modify membrane receptors or channels, influence second or third messenger systems, or alter gene expression? Lithium, a single cation, has spawned a minor industry of investigations into mechanisms of action, and the possibilities if there were numerous interacting micronutrients (the collective term for minerals and vitamins) are staggering.

My interest in this nutrient mixture was initially sparked by a case in my clinical practice. A 10-year-old with bipolar disorder was referred for treatment of severe temper tantrums, which had lasted for 2 to 4 hours daily for 4 months. The well-nourished child had no prior psychiatric history or treatment. After 2 days on the Hardy-Stephan nutrient regimen, his tantrums showed significant improvement, with the father-psychiatrist reporting a “complete” absence of outbursts or even irritability at 5 days. After 2 weeks, the available supply of the nutrient supplement was exhausted, and tantrums returned within 48 hours. A similar supplement, containing most of the same ingredients, was then started and produced a moderate improvement, which parents and teachers estimated as 60% of the original effect. When restarted on the original formula, the symptoms were judged to have again responded completely. This naturalistic A-B-A-C-B trial caught my attention because of the full stabilization without psychiatric medications and the absence of observed adverse effects.

I proceeded to cautiously conduct additional trials of the Hardy-Stephan nutrient supplement. Among 22 patients (10 adults, 9 adolescents, 3 preadolescents) who clinically met criteria for bipolar disorder, 19 showed what I judged to be a positive response (2 mild, 7 moderate, 10 marked improvement). Among the 15 patients who were being treated with medications when they began the nutritional supplement, 11 patients have been stable for 6 to 9 months without psychiatric medications. These observations are consistent with Kaplan’s open-label findings, but leave questions of safety unresolved.

Nausea was the main adverse effect in Kaplan’s study. In the larger anecdotal experience of Hardy and Stephan and my limited clinical observations, loose stools and headache were common. Diarrhea, vomiting, flatulence, and agitation were less common. Classical symptoms of mineral or vitamin toxicity were not encountered, but might have emerged with lengthier treatment or more systematic observation.

The Hardy-Stephan supplement contains many nutrients at high doses relative to the Recommended Daily Allowance (RDA), but these RDA levels were primarily established to prevent deficiency disorders in the general population. A broader range of vitamin and mineral functions (3,4) are considered in formulating the newer daily intake standards, which vary widely because of different criteria for adequacy and different health goals. (5) Although most ingredients in the nutrient supplement studied by Kaplan and colleagues appear well within safe limits, any multi – ingredient treatment might have toxic effects that cannot be readily predicted from its individual components. Even though it contains only “natural” ingredients and is not under U.S. Food and Drug Administration (FDA) purview, the Hardy-Stephan nutrient supplement should be examined in controlled empirical research – just as new pharmacologic agents are – to properly assess adverse effects and potential risks.

Psychiatrists do not normally think of vitamins or minerals as modifiers of the effects of psychiatric medications, but the early anecdotal experience with this nutrient supplement suggests that there may be strong micronutrient-medication interactions. This mineral-vitamin supplement seems to generally potentiate the clinical properties of psychiatric drugs. Most patients in the Kaplan et al. study could be managed with less medication after the nutrient supplement was added. To avoid medication toxicity, Hardy and Stephan have suggested to patients’ psychiatrists that the doses of psychiatric medications be rapidly reduced shortly after the nutrient supplement is initiated. In my observations, transitioning patients from medications to micronutrients is exceedingly tricky to manage. Introducing micronutrients too quickly can increase the adverse effects of medications, including agitation, while withdrawing psychiatric medications too quickly can result in symptom exacerbation. Often, both increased adverse effects and symptom resurgence are seen at once. Much more data are needed about how to “transition” patients who are currently taking psychiatric medications. Although it appears less difficult to treat medication-naive patients (such as my 10-year-old patient), the transition from psychiatric medications to micronutrients can require genuine technical savvy-even for patients who have not taken such medications for several weeks or months. Clinicians who mistakenly approach these new findings as encouragement to combine micronutrients with psychiatric medications may find that they have stepped into a serious quagmire.

Although health food advocates have made numerous claims without scientific documentation, nutritional influences on mental illness have received considerable research attention, (6) some of which is quite rigorous and promising. Andrew Stoll’s research on omega-3 fatty acids for bipolar disorder (7,8) and Eugene Arnold’s work on omega-6 fatty acids for attention deficit disorder (9-11) suggest that these nutrients might themselves be therapeutic. Other micronutrients (calcium, chromium) and macronutrients (inositol, amino acids) have also shown some potential for influencing mood disorders. (12-15) Arnold’s recent findings suggest that relative zinc deficiency might explain why some patients with ADHD do not show a more robust response to psychostimulants. (9)

Several large-scale double-blind placebo-controlled studies of RDA or high-dose multivitamin regimens in adults have reported improved scores of mood and cognition (16,17) as well as anxiety and somatic symptoms. (18) A recent review reported that 10 of 12 randomized double-blind placebo- controlled studies found that multi-micronutrient regimens can improve cognitive functioning in children. (19) However, high-dose multivitamin treatments have not been found to be effective in children with ADHD or learning disorders. (11,20)

Speculatively, there is a great deal to learn about minerals and vitamins in psychiatric pathophysiology and psychopharmacology. It is intriguing that many of the enzymes proposed as target sites of lithium action are metalloenzymes that are noncompetitively inhibited by lithium, which probably acts by displacing the divalent cation. (21) Why would supplementation with divalent cations have a therapeutic effect? Do we know enough about complex intracellular regulatory interactions to answer this question? Individual micronutrients will need to be examined in combination with lithium, but it is unlikely that the physiology will be so simplistic and dyadic. The groundbreaking approach of examining several nutrient ingredients at once, while a violation of our usual tenets of investigation, may present an opportunity to examine how micronutrients might operate in concert.

Assessing the safety and efficacy of multinutrient formulas will require considerable research. Developing dose-effect curves for each micronutrient, and examining all possible combinations of micronutrients, will be a horrifically large task. (22) Many years will be required to arrive at a formula that is optimal for the general population, but it is more likely there will eventually be different formulas whose safety and efficacy are optimized to the metabolic requirements of treating different disorders, different individuals, different ages, and different comorbid health situations.

The possibility of a nutritional alternative to drug treatment may raise hope and carry the risk of igniting public interest beyond reasonable bounds. Some patients may find it difficult to wait for nutrient supplements to be examined in humans for both efficacy and safety in controlled trials, and clinicians will need to help patients keep their enthusiasm from pushing usage beyond its scientific basis. Similarly, clinicians will want to think twice if they are tempted to forge ahead with empirical trials of this novel treatment with possible unknown risks and unproven benefit. Some physicians, presuming a low risk of toxicity, may reason that it is judicious to allow some drug-naive patients to proceed with empirical trials of nutrient supplements for a few weeks before committing them to treatment with psychiatric medications. Most clinicians will want the reassurance of systematic safety data before beginning to examine its effects in patients. Clinicians will hopefully minimize risks of nutrient-medication interactions by initially restricting their trials to patients who have not recently used psychiatric medications.

If Kaplan and colleagues’ preliminary findings are confirmed in controlled research, and if safety studies are favorable, what then? What if some psychiatric patients could be treated with inexpensive vitamins and minerals rather than expensive patented pharmaceuticals? or what if some doses of psychiatric drugs could be reduced by the concurrent use of nutrients? The economic implications, for individual patients and for the pharmaceutical industry, are difficult to overlook. For now, micronutrient treatments and other nutritional approaches remain in a very early stage of scientific investigation. Depending on how this line of research develops, clinicians and researchers may need to rethink the traditional bias against nutritional supplementation as a potential treatment for major psychiatric disorders.

REFERENCES

1. Kaplan BJ, Simpson JSA, Ferre RC, et al. Effective mood stabilization with a chelated mineral supplement: an open-label trial in bipolar disorder. J Clin Psychiatry 2001;62:936-944

2. Shaldubina A, Agam G, Belmaker RH. The mechanism of lithium action: state of the art, ten years later. Prog Neuropsychopharmacol Biol Psychiatry 2001;25:855-866

3. Mertz W. A perspective on mineral standards. J Nutr 1998:128(suppl 2): 375S-378S

4. Cashman KD, Flynn A. Optimal nutrition: calcium, magnesium and phosphorus. Proc Nutr Soc 1999;58:477-487

5. Mertz W. Three decades of dietary recommendations. Nutr Rev 2000;58: 324-331

6. Werbach MR. Nutritional Influences on Mental Illness: A Sourcebook of Clinical Research. 2nd ed. Tarzana, Calif: Third Line Press; 1999

7. Stoll AL, Locke CA, Marangell LB, et al, Omega-3 fatty acids and bipolar disorder: a review. Prostaglandins Leukot Essent Fatty Acids 1999;60: 329-337

8. Stoll AL, Severus E, Freeman MP, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56:407-412

9. Arnold LE, Pinkham SM, Votolato N. Does zinc moderate essential fatty acid and amphetamine treatment of attention-deficit/hyperactivity disorder? J Child Adolesc Psychopharmacol 2000;10:111-117

10. Arnold LE. Alternative treatments for adults with attention-deficit hyperactivity disorder (ADHD). In: Wasserstein J, Wolfe LE, Lefever FF, eds. Adult Attention Deficit Disorders: Brain Mechanisms and Life Outcomes. New York, NY. New York Academy of Sciences; 2001:310-341

11. Arnold LE. Treatment alternatives for attention-deficit/hyperactivity disorder. In: Jensen PS, Cooper J, eds. Diagnosis and Treatment of ADHD: An Evidence-Based Approach. Washington, DC: American Psychiatric Press. In press

12. Levy NA, Janicak PG. Calcium channel antagonists for the treatment of bipolar disorder. Bipolar Disord 2000;2:108-119

13. McLeod MN, Golden RN. Chromium treatment of depression. Int J Neuropsychopharmacol 2000;3:311-314

14. Chengappa KN, Levine J, Gershon S, et al. Inositol as an add-on treatment for bipolar depression. Bipolar Disord 2000;2:47-55

15. Van der Does AJ. The effects of tryptophan depletion on mood and psychiatric symptoms. J Affect Disord 2001;64:107-119

16. Benton D, Fordy J, Haller J. The impact of long-term vitamin supplementation on cognitive functioning. Psychopharmacology (Berl) 1995; 117: 298-305

17. Benton D, Haller J, Fordy J. Vitamin supplementation for 1 year improves mood. Neuropsychobiology 1995;32:98-105

18. Carroll D, Ring C, Suter M, et al. The effects of an oral multivitamin combination with calcium, magnesium, and zinc on psychological well-being in healthy young male volunteers: a double-blind placebo-controlled trial. Psychopharmacology (Berl) 2000; 150:220-225

19. Benton D. Micro-nutrient supplementation and the intelligence of children. Neurosci Biobehav Rev 2001;125:297-309

20. Arnold LE. Treatment alternatives for attention-deficit hyperactivity disorder (ADHD). J Arm Disord 1999;3:30-48

21. Phiel CJ, Klein PS. Molecular targets of lithium action. Annu Rev Pharmacol Toxicol 2001;41:789-813

22. Pryor WA. Vitamin E and heart disease: basic science to clinical intervention trials. Free Radic Biol Med 2000;28:141-164

Effective Mood Stabilization With a Chelated Mineral Supplement

Effective Mood Stabilization With a Chelated Mineral Supplement:
An Open-Label Trial in Bipolar Disorder

Bonnie J. Kaplan, Ph.D.; J. Steven A. Simpson, Ph.D., M.D.;
Richard C. Ferre, M.D.; Chris P, Gorman, M.D.;
David M. McMullen, M.D.; and Susan G. Crawford, M.Sc.

Background: To determine in open trials the therapeutic benefit of a nutritional supplement for bipolar disorder.

Method: The sample consisted of 11 patients with DSM-IV-diagnosed bipolar disorder aged 19 to 46 years, who were taking a mean of 2.7 psychotropic medications each at study entry. Three additional patients dropped out prematurely. The intervention is a broad-based nutritional supplement of dietary nutrients, primarily chelated trace minerals and vitamins, administered in high doses. At study entry and periodically thereafter, patients were assessed with the Hamilton Rating Scale for Depression (HAM-D), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS).

Results: For those who completed the minimum 6-month open trial, symptom reduction ranged from 55% to 66% on the outcome measures; need for psychotropic medications decreased by more than 50%. Paired t tests revealed treatment benefit on all measures for patients completing the trial: HAM-D mean score at entry = 19.0, mean score at last visit = 5.4, t = 5.59, df = 9, p .80) for each measure. The number of psychotropic medications decreased significantly to a mean SD of 1.0 1. 1 (t = 3.54, df = 10, p
Conclusion: Some cases of bipolar illness may be ameliorated by nutritional supplementation. A randomized, placebo-controlled trial in adults with bipolar I disorder is currently underway, as well as open trials in children.

Solid scientific research shows that many dietary nutrients, including minerals and vitamins, are essential for normal brain function. For instance, deficient levels of various B vitamins are related to pathologic brain and behavior disorders ranging from Korsakoff’s syndrome to pellagra. Recent work on folic acid (vitamin B,) suggests that low levels may be associated with depressive symptomatology and poor response to antidepressant medication. Less is known about the role of trace elements, but there is considerable evidence that these too may be essential for normal brain function. Zinc provides a good example. Most of the excitatory neurons of the cerebral cortex have glutamate as their primary transmitter. One type of glutaminergic neuron accumulates zinc within vesicles at axon terminals and releases it into the synapse upon firing. The precise roles of zinc in synaptic function are not known, although its presence is certain, and there are zinc-binding sites on one subset of glutamate receptor called the NMDA (N-methyl-D-aspartate) receptor. Zinc, copper, and magnesium all appear to play important modulatory roles in controlling the NMDA receptor, which has been implicated in various forms of cortical plasticity, including learning. It is possible, then, that decreased levels of some minerals in the brain may produce abnormal NMDA-mediated plasticity and subsequent abnormalities in behav-

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Patient, Heal Thyself

Patient, Heal Thyself

Business Week
BY SUSAN GARLAND
10-16-2000

Biofeedback moves toward the mainstream

Stroke survivors who are partly paralyzed have a tough time re-educating muscles to respond to mental cues. Biofeedback, a technique much derided by physicians in the past, is proving to be a most effective teaching aid. A patient’s hand, say, is hooked up to a machine that measures muscle tension. The patient then tries to close her hand. Her mind tells the muscle to tighten. The hand doesn’t move.

But a blip appears on the computer screen: A firing has occurred in the muscle, just the sort of feedback the patient needs to keep trying. After a number of sessions the blips get bigger, and eventually the hand responds. Says Rob Kall, a biofeedback practitioner in Newtown, Pa., whose Web site, futurehealth.org, promotes the method: “It gives them information that’s essential to the learning process.”

Such successes are now moving the technique from the fringes of alternative treatment into mainstream medicine. Biofeedback helps teach patients to regulate, consciously, such functions as heart rate, blood pressure, body temperature, and even brain wave patterns. Physiological data on a computer screen create a positive-reinforcing feedback loop that helps people learn basic techniques more quickly (table). Eventually, patients can alter their physiological responses without the machine.

Thanks to a growing body of data that shows the technique to be effective, people are increasingly turning to biofeedback to help treat about 150 conditions, including epilepsy, incontinence, hypertension, migraine headaches, chronic pain, and attention deficit disorder (ADD). Some doctors are sending patients to biofeedback practitioners, and hospitals are adopting the technique for certain ailments.

Even insurance companies are starting to cover it. A biofeedback session costs from $50 to more than $100, and a course of treatment can range from four sessions to more than 50. Bob Whitehouse, a practitioner in Boulder, Colo., who follows insurance trends for the Biofeedback Certification Institute of America, says that about half of the major medical companies now cover biofeedback treatments for some 40 conditions.

Many doctors are still skeptical. They argue that claims of dramatic results are not backed up by the kind of costly, controlled studies that pharmaceutical companies conduct on their products. But the National Institutes of Health has endorsed biofeedback to alleviate tension headaches and insomnia. A San Francisco State University study found that asthma patients who used biofeedback to learn new breathing techniques suffered fewer attacks and used less medicine. A study reported in the Journal of the American Medical Association noted a large decline in urinary incontinence. And biofeedback techniques developed by NASA to help astronauts handle space sickness are being used to treat people with severe and chronic vomiting.

Dr. Naras K. Baht, an internist and cardiologist in Concord, Calif., uses biofeedback as part of his treatment of heart disease. He says area cardiologists send patients to his program, which also includes meditation and seminars on stress reduction. “Anger and stress are major players in producing heart attacks,” he says. “Biofeedback helps people unlearn their anger patterns.”

The fastest growing area of biofeedback uses an electroencephalogram (EEG) to measure brain wave activity. Sometimes called neurofeedback, it’s used to treat depression, epilepsy, and migraines. The technique also shows great promise for people with ADD.

Pioneering work by Joel Lubar, a psychology professor at the University of Tennessee, shows that many kids suffering from ADD exhibit low-frequency brain waves. As their brain waves rise in frequency, they’re able to concentrate better. Biofeedback practitioners have rigged up software that shows brain wave activity as a simple computer game, such as a maze, instead of as a boring line graph. Higher-frequency waves make a figure move through the maze. So when the child concentrates, the figure moves. When the child stops concentrating, the frequency falls and the figure stops moving.

Adults as well as kids who’ve undergone EEG therapy have improved attention spans, do better at school and work, and are less dependent on such medications as Ritalin. A 10-year followup shows that these improvements last, Lubar says.

More radical is a way of sending radio waves back through the EEG to force a patient’s brain waves into new patterns. Mary Lee Esty, a Washington biofeedback practitioner, is using this technique to help fibromyalgia patients, who suffer from chronic fatigue and muscle pain. Her Neurotherapy Center of Washington is sharing a $1 million grant, with Chicago’s Rush-Presbyterian-St. Luke’s Medical Center, to study whether fibromyalgia, long considered an immune disorder, is actually a neurological condition treatable by changing brain wave patterns.

Esty used her technique to treat Linda McBee, who sustained a brain injury in a 1992 car accident. Because she suffered from chronic pain and an inability to concentrate, McBee had to give up her job in Baltimore. She lived on morphine, muscle relaxants, and anti-seizure medication. But after a year of Esty’s treatments, McBee, 37, is no longer on medication, has a job with a financial adviser–and is studying for her stockbroker exam. “I went swing dancing the other night and then went to work the next day,” she says proudly.

If you’re considering biofeedback, check with your doctor first: Insurers typically require a referral from a physician or a psychologist before they’ll cover a treatment. And you’ll want a diagnosis, to rule out conditions that can only be treated medically.

Check out practitioners with the Biofeedback Certification Institute of America (table), which makes providers meet rigorous requirements. “It’s an unregulated field,” says Judy Crawford, the institute’s director of certification. “Anyone can take a weekend course in biofeedback and hang up a shingle.” And when questioning a practitioner about success rates, ask for objective studies on the therapy’s effectiveness.

With mounting evidence that biofeedback can help alleviate many disorders, it may be just a question of time before physicians accept it as standard practice. Meanwhile, patients with nagging symptoms that won’t go away may discover that mind can indeed prevail over matter.

ASSOCIATION OF APPLIED PSYCHOTHERAPY AND BIOFEEDBACK
www.aapb.org
303 422-8436

BIOFEEDBACK CERTIFICATION INSTITUTE OF AMERICA
www.bcia.org
303 420-2902

FUTUREHEALTH
www.futurehealth.org
215 504-1700

THE BIOFEEDBACK NETWORK
www.biofeedback.net
610 933-8145

How It Works

Biofeedback helps teach patients to regulate, consciously, such bodily functions as heart rate, blood pressure, temperature, and even brain wave patterns. Here’s what happens:

* A therapist attaches sensors to the patient’s body to monitor physiological responses–an electrode on the chest, for instance, measures heart rate
* The readings are displayed, usually on a computer screen, for the patient to see
* The therapist teaches the patient techniques–such as deep breathing, simple exercises, or visualization–to help alter the readings
* The readings on the screen give the patient feedback about how well the techniques are succeeding
* Patients must spend hours practicing the techniques on their own
* Eventually, they’re able to alter their physiological responses without the machine

Doctor Vale Guyer discusses treatment of depression

Pathway to health. (Doctor Vale Guyer discusses treatment of depression)

Saturday Evening Post
SerVaas, Cory; 03-01-1998

Guest physician Dr. Dale Guyer combines traditional and alternative methods in the treatment of common health problems.

Editor’s Note: In 1997, the Post featured a series of TV health shows exploring the growing field of complementary medicine. Response from TV viewers was overwhelming. We invited Dr. Guyer back to share his knowledge from clinical work in both the traditional and complementary fields of medicine.

Q. Could you please tell us about St. John’s Wort?

A. St. John’s Wort is an extract from a common plant that is used in hedgerows in Europe and seems to be useful in the treatment of depression and certain types of anxiety disorders. In some clinical studies, it has been shown to have potential as an immune-boosting agent that can be of help for patients in treating infections. Certain injectable extracts of the plant may have efficacy in treating HIV disease. Of course, this is a pure, pharmaceutical-grade extract of the plant, so it would not be something that a person could get the same results from by using homegrown herbal decoctions. The standardized herbal extracts that are used as prescription medicines in Europe for the treatment of depression are subject, to very high quality purification processes. You may not get the same physiological effect by taking an over-the-counter herbal preparation. They are very different substances.

Q. Is it called St. John’s Wort in Germany?

A. Hypericum is another name that is often used. The concept of St. John’s Wort often creates a lot of interest. The word “wort” in our culture has a different visual picture. It is actually an old word for “root.”

Q. It’s more popular right now in Europe than it is in the United States, is that right?

A. That’s true. It relates to an interesting enigma. In our culture, the FDA gives us permission to use certain medications, but it has fairly stringent criteria for bringing a new drug to the marketplace. In Europe, particularly in Germany, there are separate regulatory agencies for natural compounds. Despite the fact that there exists a lot of data to support the use of St. John’s Wort, most of it is published in Europe and oftentimes not in the English language, so a lot of the information tends to be unavailable to physicians who practice in this country. The unfortunate part is that this information gap puts physicians at a disadvantage because they just don’t have the information or background to know how to prescribe the herb, nor do they have the confidence gained from clinical experience. An interesting observation I’ve noted is that oftentimes in our country, the medical consumer has a better source of information and education as it relates to natural products than do most physicians.

Q. Physicians would be concerned about the quality of the product.

A. True, product reliability is a major concern regarding many of the natural substances. There have been several studies where products are bought off the shelves, then assayed by an independent lab in order to determine how much of the active ingredient of a compound is actually in, for example, a capsule. The range is pretty dramatic to the point that certain herbal extracts might not even have the same herb that is advertised on the label; they might not have the same type of extract, or might not have the active components present. All these problems are improving. We have a lot of good companies and quality products out there. We also have many high-quality health- food stores. And many of the people who run these establishments are very well educated and can effectively direct a client or customer to the best-quality supplements.

Q. What should the consumer look for in buying St. John’s Wort?

A. When you are looking at any herbal medicine like St. John’s Wort, make sure it is a standardized extract. It will usually be stated on the label. For example, HyperiMed is a product made by PhytoPharmica. It clearly says on the label: St. John’s Wort 300 mg, standardized to contain 0.3% hypericins, which is thought to be the active ingredient in the herbal product. It will have some sort of verification. In some cases, it will state that it is verified by a high-pressure liquid chromatography (HPLC), which is one way to standardize the active chemical constituents. There should also be an expiration date and some assurance of quality. For a consumer who might have questions, it is very reasonable to call a company and ask for verification that a product has been independently assayed: request the source of the extracts, and so forth. Any good, reputable company can supply that information. This way, you have a lot more assurance that you are getting a quality product.

Q. The reason that many people take St. John’s Wort is that they are not afraid of its side effects, but they are afraid of the side effects of prescription drugs.

A. Side-effect profile is certainly an interesting concept. There is a book that I once read called Life Extension by Sandy Shaw and Durk Pearson. One of my favorite chapters in the book was titled, “Is there anything in the world that is absolutely safe?” The only word in the chapter was “No.”

There is an assumption in the mind of the consumer that because something is natural, it is absolutely safe. Of course, we know that this is not quite accurate: many of the most toxic compounds in the world are natural compounds–arsenic, lead, mercury, etc. However, many natural substances tend to have, less propensity to have side effects than many of our standard prescription drugs. In my clinical experience, I have found that maybe 80 to 85 percent of the time, if not more, many of these very simple approaches work better and are better tolerated by most individuals than prescription medications. That is not to exclude the fact that we really need prescription medications in acute and crisis care. But three elements often missing from conventional medical care are an understanding of, information about, and experience in using some of the less-invasive therapies.

Q. If a patient comes to you who is mildly to moderately depressed, what are some other means you would use to treat this particular patient?

A. In that situation, there is often a reaction of opinion from the general medical provider’s perspective. Here’s a situation that has an emotional component, and I have eight minutes to spend with this patient, which is unfortunate. One way to effectively deal with this situation is to write a prescription for an antidepressant that might make someone feel better. But patients who have gone through this experience often tell me that they only feel better about feeling bad. They still feel bad.

Maybe a more effective route would be to look at what is contributing to the process. This culture keeps us so busy with so much stress that for a lot of people, it is often a situational issue. I think that you have to step back in a responsible way and look at the life experience of the individual and ask, What’s going on and what could change here? Is there a light at the end of the tunnel when this process is going to shift? Then you look at simple things, as well. You ask if they are exercising. Exercise is such a big key. Our bodies are designed to be very physically active, and when they are not, it changes our perspective, our immune system, and many other parameters about living an optimal life. We then look at the social-support structure and at the emotional issue with a counselor. All these things have a bearing on the individual. There is often an assumption of looking for salvation in a pill. It doesn’t occur. Salvation comes from our own responsibility. The pill can be a transitional piece that can certainly help with depression.

There are individuals with a genetic predisposition to possessing an altered genetic neurologic chemistry. Many of the people in this class might be looking at taking medication for a lifetime in order to more effectively cope with day-to-day existence. But they are not the majority of patients whom I or most other doctors see.

Q. What if a bipolar, or manic-depressive, patient came to you? They are on lithium but prefer something else, or maybe didn’t get enough results from the lithium. Does St. John’s Wort help with the depression period of a manic-depressive?

A. Lithium is a good step. It certainly has a lot of side effects, but it does offer effective therapy. That’s a very reasonable approach. You have to look at what phase of the illness that person might be going through. If it is coupled with a lot of anxiety, you might look at another herbal medicine like kava or valerian root. Other types of approaches include biofeedback training, meditation, and exercise.

Q. Is valerian root available in health-food stores?

A. Yes. Valerian root used to be harvested and manufactured by pharmaceutical companies at the turn of the century. It was used as an effective treatment for insomnia, anxiety, and related disorders. You can buy it today in most health-food stores; even Sam’s Club now has a fair supply of many of these natural compounds. You can always identify valerian root by its odor because the isovaleric acid–thought to be the active component–smells like dirty socks. Fortunately, it doesn’t make the person smell like that, but the smell tends to decrease one’s compliance with the medicine.

Q. What are some other pharmaceutical approaches to depression?

A. One of the compounds that I have found very useful in my own practice is a medicine that is approved by the FDA in this country for the treatment of Parkinson’s disease. It is known as deprenyl, or Eldepryl. Another name for it is selegiline hydrochloride. It is used in Europe and elsewhere as a treatment for depression. It works by a different mechanism than more popular drugs like Prozac and Paxil, which work on the serotonin system in the bodies. Eldepryl works on dopamine. Dopamine is a neurotransmitter that regulates much of our behavior–motivation, memory, and so forth.

The most common side effects one sees with antidepressants, especially of the serotonin type, are the sexual side effects—difficulty in achieving orgasm, for example, and other sexual dysfunction. Deprenyl, on the other hand, tends to actually have a libido-enhancing property. It seems to be more noticeable for men, but in my clinical experience, I have noticed it occurs in both genders, which is a significant plus for a lot of people looking at a medicine that would help with managing depression.

Another thing about deprenyl that I find fascinating is that it seems also to improve memory significantly. There is a growing interest in what is called life-extension medicine, which I am sure will become a medical subspecialty. Deprenyl is one of those very interesting compounds that when given to laboratory animals seems to increase their maximum lifespan, which is a fascinating concept. If you extrapolate the data from animal models to human experience, it would suggest that we might all live to be 160 or 180 years old–a significant event.

Q. Are there side effects to deprenyl?

A. Everything has side effects. The most common ones that I have seen with deprenyl are stomachache, nausea, lightheadedness, and headaches. Those are infrequent, but not unusual. Deprenyl belongs to a class of medicines called MAO (monoamine oxidase) inhibitors. Some problems can occur when patients on MAO type A inhibitors consume cheese or other foods that contain an amino acid called tyramine. Deprenyl, however, belongs to a different class. It is an MAO type B selective inhibitor, so the tendency to have those side effects is not really present until one gets to a very high dose. For the doses required to treat as an antidepressant or as memory-enhancing medicine–life- extension medicine–doses are very low, but you always have to be cautious and attentive to what’s going on.

Q. Any cheese or just aged cheese?

A. Mostly aged cheeses.

Q. The large population of senior citizens should be very interested in life extension. With the year 2000 approaching, many 80-year-olds will want to get there and beyond to see what happens.

A. Some people ask, “Why would I want to live to be 160 years old if I’m going to have all the associations of aging?” In the animal studies to date, they maintained a very active lifestyle. How you gauge that for a rat is a challenge, but you can say that they ran mazes as fast as the younger animals, didn’t lose their hair, and remained sexually active until the day they died.

Q. Our readers will be very interested in life enhancement, including maintaining the libido. It’s healthy to be active sexually.

A. Like exercise, sexuality has a lot of health benefits as well. Many compounds are thought to be members of that class of life-extension or cognition-enhancing medicines. There are medical organizations assembled to research and bring this information to the forefront. The American Academy of Anti-Aging Medicine is one. A newsletter called Smart Drug News, published by the Cognition Enhancement Research Institute in Menlo Park, California, focuses on research into cognition-enhancing medicines, often called “smart drugs.” What we don’t realize in this country is that elsewhere in the world, patients have access to many medical compounds and pharmaceuticals that can actually increase intelligence and cognitive capacity. Had I known about this when I was going through medical school, Gross Anatomy would have been much easier.

Q. My mother gave my brother okra, which for whatever reason was considered a brain food. When he was at home, she would cook okra soup. He did excel and was at the top of his class at Annapolis. What are some brain foods?

A. One example that I will mention is a compound called dimethylaminoethanol (DMAE). You have probably heard the story that eating sardines makes you more intelligent. There might be some truth to this observation. Sardines have a higher level of this DMAE. In the past, DMAE was a prescription medicine. It is now available over the counter. Many people notice that DMAE helps improve their memory, visual-spatial skills, cognitive awareness, verbal ability, and so forth.

Q. If readers wanted to know more about these subjects, how would they subscribe to the newsletter?

A. They do have a website [www.ceri.com/ sdnews.htm]. The newsletter is called Smart Drug News.

Q. We were pretty excited about Evista, Eli Lilly Company’s recently approved drug to prevent osteoporosis. It seemed to be a good alternative for women who can’t take estrogen, yet want to make sure that they don’t have a hip fracture before they are 80 years old. Osteoporosis is a major problem. Maybe how much calcium you took as a child is important in building a bank of calcium. How do you prevent osteoporosis and hip fractures?

A. Osteoporosis is, unfortunately, a big problem in this country. In addressing osteoporosis, you have to look at the individual. Dietary considerations are very important, as is the hormone status. It is less clear that estrogen contributes much to overall bone density, whereas we know that some hormones that have a more anabolic quality- -like progesterone, DHEA, testosterone, and growth hormone–will increase bone density. My first approach would be to give the patient a global endocrine evaluation: What are levels of all the hormones, not just estrogen?

But there is a common-sense element to approaching the disease as well. We can have all the hormones on board and the nutritional component-the calcium, magnesium, and so forth–in place, but if you don’t have the physiologic drive to enhance bone density, you only get so far. The physiologic drive for bone is to have a load placed on it, which comes back to weight-bearing exercise. This is a tough sell for many women. When you tell them that they need to go to the gym and pump iron, some think that they will end up looking like Arnold Schwarzenegger, which really isn’t the case. It’s not so much that they are striving to compete in a powerlifting competition or even a bodybuilding competition. It’s using the load-bearing exercise to put stress on the bone and connective tissue, and thereby increasing its strength and bone density.

Q. How do you motivate your patients to get out there and do the right kinds of exercises?

A. What I encourage them to do is to take one day at a time. Set one simple, attainable goal, such as going to the gym tomorrow and working out for ten minutes. As people make a habit of exercise, they find that the more they get involved and engaged in the exercises, the better they start to feel. They then begin to crave feeling better, as opposed to craving some of the bad habits.

Q. Do you have personal trainers who help people get on track?

A. If exercise of that capacity is a new experience, it’s definitely a good idea to work with a personal trainer who can help set up a program that meets a person’s individual needs.

Q. Could you tell us how you investigate a thyroid deficiency?

A. Thyroid dysfunction is very common. It is unfortunate that many patients have this problem, but it is not recognized. In my practice, I frequently see patients who say that they are cold all the time; gain weight easily; don’t lose weight easily; have poor exercise tolerance, decreased libido, poor concentration, dry skin, brittle nails, etc.- -basically, a textbook description of low thyroid function.

Q. Thinning outside eyebrows?

A. Lateral margins of the eyebrows are among the observations that can sometimes be made, as is lower-extremity edema and slow heart rate. The fatigue seems to be a common issue that is associated with a deficiency of thyroid hormone. We have thyroid tests that can measure hormone levels. That would probably be an adequate screen for a majority of people. However, there are many individuals who seem to have a subclinical hypothyroid picture. Their lab tests are normal, yet they have all the symptoms that we just talked about. With these individuals, a thyroid-replacement therapy is something definitely worth trying. In my clinical experience, I find that this can change someone’s life dramatically. This goes back to the issue of depression, too. There are studies now that are looking at thyroid-replacement therapy to treat depression. In many cases, it works very well. It’s unfortunate that thyroid deficiency is something that is not very commonly recognized in conventional medicine.

Q. It is an underdiagnosed affliction.

A. Certainly underdiagnosed.

Q. A lot of people are now on low-salt diets, and noniodized salt is probably cheaper in restaurants and canneries than iodized salt. Are some people possibly not getting enough iodine in their diets?

A. That is a real possibility. I don’t think it is as common as it used to be. Goiters and iodine deficiency used to be endemic in some areas of the country many years ago. However, there are situations in which individuals have a higher-than-usual metabolic need for certain nutrients, and there are tests that determine this. Iodine is no exception. Iodine supplementation, itself, can be a very effective treatment for fibrocystic breast disease, certain problems of ovarian function, and so forth. We tend to think of iodine as only functioning for the thyroid, but actually it is also used in many other areas of the body. The ovaries are a good example. If I remember my physiology correctly, ovaries are the second most prolific users of iodine, as far as organs, in our body.

Q. In men, the prostate uses zinc. Where is the zinc pump in women?

A. What we know is that prostate tissue tends to have a lot of zinc in it. Exactly what the role might be is a little less clear, but we do know that zinc is involved in the hormonal regulations of the male androgens. It is also involved with hormonal regulation in women. Like many of the other trace minerals, we don’t know all of the activities and how zinc is used. There are so many trace minerals- -such as vanadium, strontium, boron, and so forth–whose activities are less well defined, partially because we need such small quantities of these nutrients to maintain normal health that it is very difficult to delineate where it is functioning in the body.

Q. There is a Purdue man who has good evidence that for some people, copper is able to help with their arthritis. A. Copper bracelets do help a lot of people with their arthritis. Using a copper supplement can be helpful for some people. There is some research that would suggest that antiinflammatory drugs commonly prescribed to treat the pain associated with arthritis only work as they bind to a copper ion in the body. Copper seems to play a big role in our bodies. We know that it is used as an enzymatic cofactor for cross-linking collagen, which adds structural integrity to our connective tissues, circulatory system, and any place collagen is used. Although copper has many benefits, we don’t want to overdo it, either, because copper is thought to be one of those ions like iron that generates free radicals. It’s an example of balance. Everything is best in balance. If you get too low, there are problems. If you get too high, there are potential side effects as well.

Q. I have always wondered why they didn’t put copper in the soles of their shoes where it wouldn’t show, instead of wearing copper bracelets around their wrists and letting their skin turn colors.

A. That’s a new marketing concept that could go over big.

What Is SAMe

Newsweek
July 5, 1999

By Geoffrey Cowley and Anne Underwood

She was making lunch for herself and a friend one Saturday this spring when an unfamiliar feeling swept over her. The 50-year-old social worker had fallen deep into depression two years earlier, and had given up on prescription antidepressants when the first one she tried left her sluggish, sexually dormant and numb to her own emotions. Then, in mid-March, she heard about a naturally occurring substance called SAMe (pronounced “Sammy”). She had been taking it for just a few days when she began setting the table that Saturday morning. A ginger-miso sauce was chilling in the fridge, and she was garnishing her finest plates with fresh anemones. Suddenly, there it was: a sense of undiluted pleasure.

This woman (who asked not to be named) has taken SAMe ever since, and her mood isn’t the only thing that has changed. Until this spring she took prescription-strength anti-inflammatories for her arthritis, and still had trouble bending her knees. She’s now off those drugs – and feeling more nimble than she has in 20 years.

Could an over-the-counter tonic really do all this? Pills purporting to cure everything from hemorrhoids to hangnails are usually worthless and sometimes dangerous. And because SAMe has not been studied extensively in the United States, many doctors are leery. Beware, says Dr. Gilbert Ross of the American Council on Science and Health, a conservative watchdog group. Supplement dealers are once again trying to “flimflam the public into using untested remedies instead of FDA-approved pharmaceuticals.”

The Food and Drug Administration has not rigorously evaluated SAMe, let alone approved it. (Federal law permits the unregulated sale of naturally occurring substances as long as marketers avoid therapeutic claims.) And the studies that researchers have conducted are not of the magnitude the FDA would require for a drug approval. But that doesn’t mean SAMe is “untested.” In dozens of European trials involving thousands of patients, it has performed as well as traditional treatments for arthritis and major depression. Research suggests it can also ease normally intractable liver conditions. SAMe doesn’t seem to cause adverse effects, even at high doses. And doctors have prescribed it successfully for two decades in the 14 countries where it has been approved as a drug.

Until recently, few Americans had heard of the stuff. An Italian firm developed it as a pharmaceutical in the early 1970s but lacked the will or the resources to make a run at a drug approval in the United States. Then, this spring, two U.S. vitamin companies, GNC and Pharmavite, started importing large quantities of SAMe to sell as a supplement. The product took off quickly—Pharmavite’s Nature Made brand now ranks 25th among the 13,000 supplements sold in grocery and drugstores—and the impact is still growing. When you consider that some 50 million Americans suffer from arthritis or depression, the implications are staggering.

SAMe (known formally as S-adenosylmethionine) is not an herb or a hormone. It’s a molecule that all living cells, including our own, produce constantly. To appreciate its importance, you need to understand a process called methylation (chart). It’s a simple transaction in which one molecule donates a four-atom appendage—a so-called methyl group—to a neighboring molecule. Both the donor and the recipient change shape in the process, and the transformations can have far-reaching effects. Methylation occurs a billion times a second throughout the body, affecting everything from fetal development to brain function. It regulates the expression of genes. It preserves the fatty membranes that insulate our cells. And it helps regulate the action of various hormones and neurotransmitters, including serotonin, melatonin, dopamine and adrenaline. As biochemist Craig Cooney observes in his new book, “Methyl Magic,” “Without methylation there could be no life as we know it.”

And without SAMe, there could be no methylation as we know it. Though various molecules can pass methyl groups to their neighbors, SAMe is the most active of all methyl donors. Our bodies make SAMe from methionine, an amino acid found in protein-rich foods, then continually recycle it. Once a SAMe molecule loses its methyl group, it breaks down to form homocysteine. Homocysteine is extremely toxic if it builds up within cells. But with the help of several B vitamins (B6, B12 and folic acid), our bodies convert homocysteine into glutathione, a valuable antioxidant, or “remethylate” it back into methionine.

SAMe and homocysteine are essentially two versions of the same molecule—one benign and one dangerous. When our cells are well stocked with B vitamins, the brisk pace of methylation keeps homocysteine levels low. But when we’re low on those vitamins, homocysteine can build up quickly, stalling the production of SAMe and causing countless health problems. High homocysteine is a major risk factor for heart attack and stroke. During pregnancy, it raises the risk of spina bifida and other birth defects. And many studies have implicated it in depression.

How, exactly, might taking extra SAMe improve a person’s mood? Researchers have identified several possibilities. Normal brain function involves the passage of chemical messengers between cells. SAMe may enhance the impact of mood-boosting messengers such as serotonin and dopamine—either by regulating their breakdown or by speeding production of the receptor molecules they latch on to. SAMe may also make existing receptors more responsive. These molecules float in the outer membranes of brain cells like swimmers treading water in a pool. If the membranes get thick and glutinous, due to age or other assaults, the receptors lose their ability to move and change in response to chemical signals. By methylating fats called phospholipids, SAMe keeps the membranes fluid and the receptors mobile.

Whatever the mechanism, there is little question that SAMe can help fight depression. Since the 1970s, researchers have published 40 clinical studies involving roughly 1,400 patients. And though the studies are small by FDA standards, the findings are remarkably consistent. In 1994 Dr. Giorgio Bressa, a psychiatrist at the University Cattolica Sacro Cuore in Rome, pooled results from a dozen controlled trials and found that “the efficacy of SAMe in treating depressive syndromes… is superior [to] that of placebo and comparable to that of standard… antidepressants.”

This isn’t the first natural substance to show promise as a mood booster. Small studies suggest that St. John’s wort can ease low-grade melancholy, but SAMe has been tested against far more serious disorders. In one of several small U.S. studies, researchers at the University of California, Irvine, gave 17 severely depressed patients a four-week course of SAMe (1,600 mg daily) or desipramine, a well-established antidepressant. The SAMe recipients enjoyed a slightly higher response rate (62 percent) than the folks on desipramine (50 percent).

No one has found SAMe significantly more effective than a prescription antidepressant, but it’s clearly less toxic. The drugs that predate Prozac (tricyclics and MAO inhibitors) can be deadly in overdose, or in combination with other medications. Newer antidepressants, such as Prozac, Zoloft and Paxil, are less dangerous, but their known side effects range from headaches and diarrhea to agitation, sleeplessness and sexual dysfunction. And SAMe? Studies suggest that like other antidepressants, it may trigger manic episodes in people with bipolar disorder. Aside from that, the most serious side effect is a mild stomach upset.

Until large U.S. studies confirm these findings, few American doctors will recommend SAMe to severely depressed people. “The evidence looks promising,” says Harvard psychiatrist Maurizio Fava, “but it’s not definitive. In some European countries they have different marketing standards than we do.” UCLA biochemist Steven Clarke echoes that concern, saying the nation is embarking on a large, uncontrolled experiment in which consumers are the guinea pigs. A key concern is that depressed patients will drop other treatments to try SAMe, and end up suicidal. Columbia University psychiatrist Richard Brown warns of that hazard in “Stop Depression Now,” a new book coauthored with Baylor University neuropharmacologist Teodoro Bottiglieri. Yet Brown himself has treated several hundred patients with SAMe in recent years, sometimes combining it with other drugs, and he has never had a bad experience. “It’s the best antidepressant I’ve ever prescribed,” he says flatly. “I’ve seen only benefits.”

If the world needs a better antidepressant, it could also use a better arthritis remedy. Nearly a third of the 40 million Americans with chronic joint pain use drugs like aspirin and ibuprofen. In arthritis-strength doses, these so-called NSAIDs, or nonsteroidal anti-inflammatory drugs, can have devastating gastric side effects. Some 103,000 Americans are hospitalized annually for NSAID- induced ulcers, and 16,500 die. Even when NSAIDs don’t destroy the digestive tract, they may ultimately worsen people’s joint problems, for they slow the production of collagen and proteoglycans, the tissues that make cartilage an effective shock absorber.

Could SAMe provide an alternative? In a dozen clinical trials involving more than 22,000 patients, researchers have found SAMe as effective as pharmaceutical treatments for pain and inflammation. But unlike the NSAIDs, SAMe shows no sign of damaging the digestive tract. And instead of speeding the breakdown of cartilage, SAMe may help restore it. You’ll recall that after giving up its methyl group, SAMe becomes homocysteine, which can be broken down to form glutathione (the antioxidant) or remethylated to form methionine (the precursor to SAMe). As luck would have it, the reactions that produce glutathione also yield molecules called sulfate groups, which help generate those joint-sparing proteoglycans.

What does this mean for patients? The Arthritis Foundation, a mainstream advocacy group, recently said its medical experts were satisfied that SAMe “provides pain relief” but not that it “contributes to joint health.” The evidence that SAMe can repair cartilage is admittedly preliminary, but it’s intriguing. When German researchers gave 21 patients either SAMe or a placebo for three months, using MRI scans to monitor the cartilage in their hands, the SAMe recipients showed measurable improvements. That wouldn’t surprise Inge Kracke of Cologne. She was an active 48-year-old when a 1996 auto accident mangled her left knee and left her hobbling on a cane. Dr. Peter Billigmann of the University of Landau prescribed a regimen that combined SAMe (1,200 mg a day for three months) with injections of hyaluronic acid, a cartilage component. Cartilage injuries don’t normally heal, but a year later Kracke’s knee looked better on X-rays. She now plays golf three times a week.

SAMe may have other benefits as well. Studies suggest it can help normalize liver function in patients with cirrhosis, hepatitis and cholestasis (blockage of the bile ducts). SAMe has also been found to prevent or reverse liver damage caused by certain drugs. As patients hear more about this supplement, they may try treating themselves for all these conditions and others. But many of them will be disappointed—either because they expect miracles that SAMe can’t deliver, or because they take the wrong dose or form.

The first challenge is to buy full-strength SAMe. “Some companies are very reliable manufacturers,” says Dr. Paul Packman of Washington University in St. Louis. “But some aren’t. You can’t always tell from the label on the bottle how much active ingredient is actually in it.” Pharmaceutical-grade SAMe comes in two forms, one called tosylate and a newer, more stable form called butanedisulfonate. Only Nature Made and GNC sell the new butanedisulfonate version, but several U.S. retailers import reliable tosylate products. And because SAMe is absorbed mainly through the intestine, it’s best taken in “enteric coated” tablets that pass through the stomach intact. None of the products comes cheap. The price of a 400-mg dose ranges from $2.50 (Nature Made) up to $18.56 for an uncoated Natrol product called SAM sulfate.

Assuming you buy full-strength SAMe, the second challenge is to use it effectively. Experts advise taking it twice a day on an empty stomach, but different people may require different amounts. Though studies suggest that 400 mg a day is an effective dose for arthritis, the daily doses used in depression trials have ranged as high as 1,600 mg. Clinicians generally start people with mood problems at 400 and ratchet up as necessary.

Unfortunately, there is no convincing evidence that SAMe can make healthy people happier or more mobile than they already are. But there are lessons here for everyone. We now know that methylation is vital to our well-being. It’s equally clear that the modern Western diet—rich in protein, light on the plant foods that supply folate—is a prescription for stalling that vital process. “SAMe works as a medication to treat certain diseases,” says Paul Frankel, a biostatistician at the City of Hope National Medical Center in Duarte, Calif. “But for most people the problem is undermethylation of homocysteine.” In other words, many of us could arm ourselves against low moods, bad joints and weak hearts simply by upping our intake of B vitamins. That may sound less exciting than taking a miracle supplement. But with luck, it could keep you from ever needing one.