M O O D S

A new frontier in brain research may hold valuable clues for mood disorders, Frederick K. Goodwin M.D. told the annual conference of the National Depressive and Manic-Depressive Association on October 3 in Houston.The study of processes in the cell beyond the transmitters, synapses and receptors may yield better understanding of existing drugs and give birth to new ones, he said. And scientists may finally understand if and how early-life stress or medications alter the expression of genes.

In a follow-up interview with Moods, Dr. Goodwin, former director of the National Institute of Mental Health, said that for half a century scientific inquiry in psychiatry has focused on neurotransmitters, synapses and receptors.   “What’s opened up now,” he said, “is the realization that if we’re going to understand what’s really going on, we have to understand what happens in the cell beyond the receptor—what happens in the nucleus of the cell where the genetic material is processed. “Because the synaptic events--those we know of--the blocking of receptors, the blocking of reuptake, and the increase in transmitter levels—all occur in seconds. “Whereas the clinical effects of medications, we know, occur in weeks and months,” he continued. “So we always knew these short-term, immediate effects couldn’t be the whole story.

“So these [new] studies look at the whole cascade of postsynaptic events of what are called the second messengers. The first messengers are the transmitters like norepinephrine, dopamine, or serotonin. “The second messengers are a series of chemicals beyond the receptor, such as cyclic A and P and protein kinase C.

“To make a long story short, we’ve found that mood stabilizers like lithium and Depakote have very interesting actions on the post-synaptic, signal transduction systems—these so-called second messengers. “It appears the medications we use alter the control of these second messengers over the expression of genes in the cell. We know medications don’t change our genes. But the real question is do they change the way genes are expressed?

“To translate the genetic message, DNA, the genetic material, must be converted into RNA to manufacture specific proteins. “That conversion is controlled by a whole series of mechanisms in the cell sensitive to these signal transduction processes. In detail, it’s a complicated, constantly unfolding story. But the basic concept is rather simple. These events take long periods of time, the synthesis of new proteins resulting in the synthesis of other proteins . . ."This would explain why a drug might have such long-term effects [in weeks or months], because it would change the composition of proteins in the brain—as opposed to the neurotransmitters that are very ephemeral.

“This research into postsynaptic transduction mechanisms may do more than explain how drugs work—it may lead to new drug discoveries. “If you know, for example, that lithium and Depakote each inhibit a certain kind of phosphokinase, and if you discover other phosphokinase inhibitors that are a little bit cleaner and more specific, you could, perhaps, create drugs more specific to manic depression, with fewer side effects.

“So this has set in motion a big search for the details of these pathways. Of course, working out the details means figuring out what compounds might block or stimulate certain reactions. “It’s fascinating that these particular pathways give the most logical explanations of the long-term effect of psychosocial stress on the brain. For example, if psychosocial stress affects a transmitter and that changes the rate at which these second messengers are manufactured, and these second messengers, in turn, affect the rate at which a particular gene is turned on or off, then you can begin to understand how a critical developmental life stress in early life could make a long-term, even permanent, structural change in the brain. “Of course, this has never been adequately understood just by looking at the effect of these drugs on norepinephrine or dopamine or serotonin.’’

Dr. Goodwin said tamoxifen, an anti-cancer drug, is one example of a phosphokinase inhibitor under recent study. “It has been shown,” he said, “to be effective for acute mania.”

Dr. Goodwin is currently research professor of psychiatry at The George Washington University in Washington D.C., where he conducts research on manic-depressive illness.

From the Chair

by Rich Satkin, Chairperson of MDSG

My focus is on destigmatization. I was delighted to see a recent ad campaign stating “For People with Mental Illness, Treatment is Working” sponsored by the Mental Health Association of New York City. What a wonderful and accurate message.

First, it puts the proper emphasis on “people with mental illness” instead of stigmatizing “the mentally ill” as not people at all but illness. Second, it accurately compares mental illness to physical illness and calls attention to the fact that treatment works. Third, it fosters hopefulness through treatment.

At the recent National Depressive and Manic-Depressive Association (NDMDA) conference, Dr. Frederick Goodwin, former head of the National Institute of Mental Health, gave a marvelous talk on destigmatization. Studies have shown, he said, that a correct diagnosis of a mental illness is actually made more often than one for certain physical illnesses (60 to 80 percent in five major mood disorders compared to 40 to 50 percent in three heart diseases).

Greater diagnostic accuracy brings superior treatment efficacy. So in terms of cost-effectiveness, that hallmark of our market-based economy, it is economically as well as morally sound to induce people with mental illness to seek treatment and stay the course.

A theme heard throughout the conference was the increasing number of pharmacological treatments, often combinations of drugs that lead to successful outcomes. While this may try the patience of so-called “treatment-resistant” people, there’s reason to be hopeful especially if one has an expert and trusted psychopharmacologist.

Unfortunately the majority of people suffering from a mental illness do not seek treatment (thus adding hopelessness to their condition), a fact Dr. Goodwin attributes in great measure to stigmatization by the media, which often portray mentally ill people as bizarre, crazy or worse.

On another front, experts told conferees at NDMDA that over the next 10 to 15 years genetic research may hold important breakthroughs. Clinical implications may include better prediction of susceptibility to mood disorders, an explanation of the physiology of these disorders in the brain, and development of better-targeted drugs.

And, in the words of one presenter, “Proof at last!” that these disorders are biological in origin, and are as deserving as any “physical illness” of treatment, understanding and empathy.

Ask the Doctor     

with Dr. Ivan Goldberg 

Q. Do antidepressants have any effect on the likelihood of suicide?
A. Many studies have shown that antidepressants not only reduce the severity and duration of depressive episodes, they also reduce the likelihood of suicide by about 50 percent.
Ref: Isaacson G et al. Journal of Affective Disorders 1996, 41, 1-8.

Q. My doctor started me on Lamictal to control my rapid-cycling bipolar disorder. While the Lamictal helped me stop cycling, it left me in a moderately severe depression. So my doctor started me on Zoloft, slowly increasing the dose to 100 mg a day. Soon after starting Zoloft, I began to feel dizzy and became very unsteady on my feet. My doctor said he’d never heard of Zoloft causing these side effects. What is going on with me?
A. This may be an interaction between Zoloft and Lamictal. Zoloft may increase the blood levels of Lamictal. Higher Lamictal levels may be responsible for the dizziness and unsteadiness, side effects frequently seen when Lamictal blood levels are too high.  
Ref: Haufman, KR & Gerner R Seizure 1998, 7, 163-165.

Q. My mother is 84 years old and is being treated for coronary artery disease. She has recently become depressed, and her doctor consulted with a psychiatrist, who suggested that she take an SSRI. I don’t want her to take an SSRI, because I heard they can be very toxic for people with heart disease. Should I discourage my mother from taking one of these antidepressants?
A. Depression in elderly people is very treatable and should not be accepted simply as a natural result of growing older. While the older tricyclic antidepressants were sometimes toxic for people with coronary artery disease, the SSRIs are usually tolerated quite well by people with this disease. Treating depression in elderly people is important, because untreated depression is associated with increased mortality.
Ref: Sheline, YI et al. American Journal of Medicine 1997, 102,54-59.

The Reader’s Corner  (Book Review)

by Betsy Naylor

   NIGHT FALLS FAST: Understanding Suicide
    Kay Redfield Jamison
    Knopf, New York, 199. 432 pages. $26.00.

To the extent that anyone can understand suicide, Night Falls Fast teaches us quickly and well: what the numbers are, where the science is, and how suicidal pain feels, in the words of those who have suffered it. A wonderfully clear writer, Kay Redfield Jamison, a psychologist and professor, has also published An Unquiet Mind, her memoir, and Touched by Fire, about mood disorders and creativity. With Dr. Frederick Goodwin she wrote Manic-Depressive Illness, the definitive text on that subject.

Dr. Jamison understands suicide as a huge public health problem, getting worse among people under 25. While 17,000 Americans die each year by homicide, the number of suicide deaths is 30,000. Another half-million people require hospitalization because of suicide attempts.

In her prologue, Dr. Jamison relates how her manic-depressive illness (the term she prefers to bipolar illness), first appeared as she was finishing high school. She remembers how close she came to suicide, saved only by a lifting of her profound depression. At 28, she attempted suicide with an overdose of lithium. Afterward, she was most disturbed that she had acted as if she was well so convincingly that everyone else thought she was well.

“Each way to suicide is its own: intensely private, unknowable and terrible,” writes Dr. Jamison, beginning a chapter on the psychology of suicide. Everybody wants to understand why; friends and family ask for a very long time. Studies can give us the details of suicide such as age, sex, and season (most suicides are committed in spring and early summer), but these statistics predict very little. For any given individual, the most powerful predictor is a previous suicide attempt.

In 90 to 95 percent of suicides, a psychiatric diagnosis is found: manic depression, depression, schizophrenia, borderline or antisocial personality disorder, alcoholism, or drug abuse. There are other risk factors in this lethal mix: heredity, impulsive or violent temperament, intoxication, profound emotional upheavals, loss and disappointments, recent release from a hospital.

The strongest aspect of Night Falls Fast is the human face Dr. Jamison puts on suicide through her own experience and that of many others--some of whom we recognize from history and literature.

There is hope in suicide prevention measures: we can listen and be more closely involved with one another, especially those who are fragile. Dr. Jamison is a strong advocate of psychotherapy. People are greatly helped by a professional who cares.

Insurance programs should provide sufficient hospital and outpatient coverage. Media could portray suicide in a more complex, realistic way. And doctors and many of us could be more sensitive to pain felt by people around us. In strong enough measure, that pain makes people want to die.

While the author suggests no particular public policy measures to prevent suicide, she has produced a very readable book, guaranteed to enlighten the general public

The In-The-News section of this web site has a number of links about this book and about the author, including interviews with the author, other articles she has written and a book exerpt.

You can purchase (and read more about) Dr. Jamison's book from Amazon.com by clicking on the link below. Doing so will result in a referral fee being paid by Amazon to MDSG at no cost to you. As of November 1999, the book was selling for $18.20, but the price could change at any time.
http://www.amazon.com/exec/obidos/ASIN/0375401458/themooddisordsup

The other book mentioned in this article, Manic-Depressive Illness was published in 1990 by Oxford University Press. As of November 1999, it is selling for $78.50 at both the Amazon.com and Barnes and Noble web sites (again, the price may change). You can purchase it (and read more about it) from Amazon, by clicking on the link below. Doing so will result in a referral fee being paid by Amazon to MDSG at no cost to you.
http://www.amazon.com/exec/obidos/ASIN/0195039343/themooddisordsup  

Will Fish Oil Help Your Moods?

By Diana Ver Nooy

Although the findings are still considered preliminary, the evidence continues to mount that omega-3 fatty acids have antidepressant and mood-stabilizing properties and may have a role in the treatment of patients with mood disorders.

In a study discussed last fall on National Public Radio’s “The Infinite Mind” and published in the May 1999 issue of Archives of General Psychiatry, patients with bipolar disorder who took omega-3 fatty acid supplements in addition to their usual treatment, “had a significantly longer period of remission” than patients on usual treatment plus an inactive placebo, wrote Andrew Stoll, M.D., of McLean Hospital and Harvard Medical School.

“You are what you eat; if you eat a lot of fish you’re going to have a lot of omega-3s in your [cellular] membranes,” said Dr. Stoll at the American Psychiatric Association’s 1999 Annual Meeting in Washington D.C. in May. “That appears to be good for your heart, good for your joints, and may be good for your brain as well,” he said.

Adequate amounts of omega-3s, obtained from the diet or from fish oil capsules, cause a “general dampening” of postsynaptic signal transduction in the brain. “That’s one theory on how they work,” said Dr. Stoll, adding that there are also “many, many” other proposed theories on why omega-3s stabilize moods.

The omega-3 fatty acids include EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid, not to be confused with DHEA, an entirely different substance), Dr. Stoll explained. Changes in diet in this part of the world, “especially in this century,” have led to declining intake of EPA and DHA. “There is some evidence,” said Dr. Stoll, “that cardiovascular disease has increased in this century because of the deficiency of omega-3s.”

Rising rates of major depression “in each decade of this century, with the age of onset going down,” may also be attributable, at least in part, to “this loss of omega-3s,” he speculated. Joseph Hibbeln, M.D., of the National Institutes of Health, who found a strong correlation “between apparent fish consumption [around the world] and lower annual prevalence of major depression,” published particularly striking support for this viewpoint last year in Lancet.

In Dr. Stoll’s recently published double-blind study, 30 bipolar patients were assigned to groups that randomly received either placebo or 9.6 grams per day of omega-3 fatty acids in the form of fish oil capsules. All of the patients had been manic or hypomanic in the preceding 12 months, and about 40 percent had rapid-cycling symptoms. Existing treatments (mostly mood stabilizers such as lithium or Depakote) were continued. Although the trial was originally planned to last nine months, it was stopped after only four when it became apparent that patients taking the omega-3s were doing much better on nearly every outcome measure than the patients taking placebo. Differences in rates of relapse were particularly striking.

Although Dr. Stoll acknowledged more study is needed (and further studies are already in progress), he believes omega-3 supplementation should be considered for any bipolar patient not responding fully to other treatments.

Dietary sources of omega-3s include cod, salmon, haddock, and scallops, but it is difficult to get adequate and consistent mood-stabilizing amounts simply by eating fish. However, the omega-3 doses used in Dr. Stoll’s study are probably higher than necessary. He advises possibly “shooting for a dose of 2 to 5 grams per day,” best taken with antioxidants (e.g., vitamin E).

Some experts now believe that EPA is the most important component for mood stabilization.

Read labels carefully, because the percentage of omega-3s in some brands of fish oil may be as low as 30 percent. Some sources recommend these brands of fish oil: Solgar Mega-Max EPA, Nordic Naturals ProOmega (available at www.nordicnat.com), and omegabrite (available at www.omegabrite.com). In addition, said Dr. Stoll, “more concentrated forms will be available soon.” Cod liver oil is not recommended, because the amounts needed for adequate omega-3s would contain toxic levels of vitamin A. Omega-3s in flaxseed oil, Dr. Stoll added, have a shorter chain structure, and it is unclear whether the benefits would be the same.

Omega-3 supplementation is safe, said Dr. Stoll, with only a slight theoretical chance of increased bleeding if used in high doses in conjunction with anticoagulants. But patients with diabetes must consult their physicians before taking the supplements. "These are the only fats that do not cause weight gain,” Dr. Stoll added.

“The omega-3 story doesn’t end with bipolar disorder,” he said, citing studies suggesting benefits in schizophrenia and major depression. “This is an evolving story,” he concluded, “and you will be hearing more.”

For more information:

• Calabrese JR, Rapport DJ, Shelton MD: Fish oils and bipolar disorder: A promising but untested treatment. Arch Gen Psychiatry 1999; 56:413-414;
• Stoll AL, Marangell LB: In reply. Arch Gen Psychiatry 1999; 56:415-416.
• Hibbeln JR: Fish consumption and major depression [letter]. Lancet 1998; 351: 1213.
• Simopoulos AP, Robinson J: The Omega Diet. HarperCollins, New York. 1999.
• Stoll AL, Severus WE, 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

Diana Ver Nooy is former president of the Bergen County, New Jersey, Depressive and Manic-Depressive Support Group and editor of Neurology Reviews, a news journal for neurologists.

About  MDSG

  The Mood Disorders Support Group
  P.O. Box 30377
  New York, N.Y. 10011
  Phone_______(212) 533-MDSG
  Fax________ (212) 675-0218
  E-mail_____ info@mdsg.org
  Web________ www.mdsg.org

MDSG/NY sponsors a series of  lectures on various aspects of mood disorders. Anyone can attend our lectures. More information about our lectures is available on our lectures page at http://www.mdsg.org/lectures.html. Our next lectures are:
   Light, Air, and Those Winter Blues Michael Terman Ph.D. December 6, 1999
   ECT:  An Update  Harold A. Sackeim Ph.D.  January 10, 2000 
   Does Medication for Depression Change Personality? David Hellerstein, M.D.  February 7, 2000  
   Cognitive-Behavioral Treatment of Depression and Bipolar Disorder Elizabeth Nelson, Ph. D. March 6, 2000

The Mood Disorder Support Group depends on membership fees and contributions for its operating expenses. A one year individual membership is $35, a one year family membership is $50. Memberships and contributions to MDSG are tax-deductible to the extent allowed by law. MDSG is an IRS-recognized 501(c)(3) organization..