Special Year That Was Issue
Lead story:
A breakthrough year in genetics.
Other 2003
Developments: Treatment studies, Meds, Natural
treatments, Personality, Services, The silver screen.
Also in this issue:
Cymbalta, Grape juice for memory, Ritalin
depression link in rats, Kids, BP kids, Meditation, Two heart
studies, Psychiatric protection orders, Silver ribbon stamp,
Correction, Mailbag McMan's
Web, Donations.
DNA Sunrise
By far the number one Newsletter story this
year, with seven lead articles, concerns the breakthrough advances
in genetics/genomics. For a good 15 years, the quest for mood
genes been bogged down in the thankless task of trying to tease
out impossibly subtle anomalies from defiantly unyielding
chromosomes. Now researchers are starting to hit paydirt by
putting a range of new techniques and outlooks into practice.
Although it is way too soon to start popping the champagne corks,
this year’s developments give us every reason to be hopeful:
The first study was actually published in 2002.
Researchers at the NIMH divided 28 subjects into two groups, those
who had a short form (allele) of the serotonin transporter gene
SLC6A4, and those with the long allele. Cells with the long
variant express nearly double the serotonin reuptake as those with
the short allele. The subjects were placed in an fMRI machine and
completed a simple exercise involving processing the images of
three different faces. The brain scans revealed that those with
the short allele displayed a significantly greater response in the
right amygdala while engaged in the task. The amygdala is a tiny,
almond-shaped part of the brain which governs fear. When the
subjects were given a thinking task not involving emotions, no
variants were seen.
Newsletter 5#18 noted: "This may very well be
the first study linking genes to emotions in humans, and it
certainly won’t be the last." Lo and behold, that very same SLC6A4
featured in a University of Wisconsin/King’s College (London)
study that analyzed 14 stressful events in the lives of 847 New
Zealanders from ages 21 to 26. The study found that 33 percent of
those with one or two copies of the short allele and with four or
more life stresses developed depression as opposed to 17 percent
with two copies of the long variant. Stressed individuals with the
short allele experienced more suicidality (11 vs four percent)
than those two copies of the long allele.
That study was pushed off this Newsletter’s
front page by a finding from the University of California at San
Diego that fingered a mutation in GRK3 which may affect three
percent of bipolar families. GRK3 is believed to be involved in
the regulation of dopamine. The researchers employed linkage
analysis (an old method), animal studies, and sequencing the gene
for "single-nucleotide polymorphisms" (SNP) to establish a kind of
fix by triangulation.
Speaking of SNPs, a University of Ottawa/McGill
University study of 129 depressed patients plus 102 males who had
died from suicide found that, compared to the controls in the
study, twice as many in the depression group and four times as
many in the suicide group had a SNP variation in the serotonin 1A
autoreceptor gene. Meanwhile, University of Pittsburgh researchers
zeroed in on a gene that codes for CREB1, which may one day be a
target of a future generation of antidepressants.
"Endophenotype" research thinks outside the DSM
box and its preoccupation with the textbook symptoms of
"phenotype." University of Colorado researchers have focused on
why people with schizophrenia have trouble tuning out repetitive
sounds. This trait is not listed in the DSM-IV, but it clearly
affects a person’s ability to concentrate. The University of
Colorado team found that "auditory gating" is modulated by the
alpha7 nicotinic receptor, with linkage to chromosome 15q14.
Alpha7 is reduced in the hippocampi of patients with
schizophrenia. Mood gene research by endophenotype probably won’t
be long in coming.
Three years after producing a rough map of the
human genome, the Human Genome Project in April announced a 99
percent complete draft, coinciding with the fiftieth anniversary
of the discovery of the double helix by Watson and Crick. Said
Francis Collins MD, PhD, leader of the project: "This is a
transforming moment. This is the day we rolled out the first
edition of the Book of Life."
But the genome is turning out to be maybe the
initial chapters. Epigenetics picks up the story deeper into the
book, involving information stored in the proteins and chemicals
that surround and stick to DNA. The bad news is we know next to
nothing about epigenetics. The good news is we’re learning. In one
eye-opening study, it was discovered that one identical twin with
schizophrenia had more in common, epigenetically, with a different
set of ill twins than his own nonaffected twin.
It may take decades before we see any clinical
application involving genes, but a taste of the future was offered
in an American Journal of Psychiatry article by Robert Sapolsky
PhD of Stanford, who is working on transporting modified gene
material into the hippocampi and amygdala of lab animals. The idea
is that in response to stress, the new gene material will program
other parts of the brain and nervous system into coping with
crisis instead of triggering a mood-busting flight-or-fight
response.
Bring on 2004.
Also from 2003
The year 2003 featured a trio of studies that
takes a little bit of the guesswork out of treatment. A study by
Altshuler et al found that for those bipolar patients who
responded well to an antidepressant it was better to stay on their
antidepressant than go off. The catch? Only 34 percent of the
study population had a good initial response to their
antidepressant in the first place and only 15 percent benefited
from long-term treatment. Moreover, we have no way of knowing in
advance which 15 percent will benefit. Hopefully, the study will
inspire someone to find out.
Meanwhile, for unipolar depression, an Oxford
and other centers meta-analysis of 32 trials involving 4,410
patients found that those who continued on their antidepressant
reduced the risk of relapse by 70 percent.
Finally, a secondary analysis by Nemeroff et al
of a 2000 study found that those depressed women who experienced
childhood trauma fared significantly better on talking therapy
than on an antidepressant. This study raises the hope that a very
significant subset of depressed patients can be identified and
appropriately treated, with a much improved chance of success.
Meds on Parade
The major development on the drug front this
year was Eli Lilly's continuing combination Zyprexa-Prozac (Symbyax)
full court press for treatment-resistant depression and bipolar
depression. Cynics would say that Lilly is simply looking for a
new way to milk its expired Prozac patent, but should the company
succeed with its FDA application, depressed bipolar patients will
have an alternative to Lamictal. Other companies are looking to
follow Lilly’s lead.
Three FDA approvals this year: Lamictal for
bipolar maintenance (particularly depression), and Risperdal for
acute (initial phase) bipolar mania and mixed episodes, and
Zyprexa (previously approved for acute mania) for combination
acute mania therapy. In Europe, Seroquel and Zyprexa were approved
to treat mania.
The major surprise was Merck bailing out on its
much-ballyhooed substance P antidepressant, Emend, in the phase
III trial phase.
The FDA instructed drug manufacturers to put
diabetes warnings on Zyprexa and other atypical antipsychotics.
Meanwhile, after a review of the clinical trials, UK authorities
warned that kids should not be on antidepressants except for
Prozac. The FDA is undertaking a similar review.
Natural
Studies involving natural substances are few and
far between. A Finnish study of 115 depressed outpatients being
treated with antidepressants found that those who responded fully
to treatment had higher levels of vitamin B12 in their blood at
the beginning of treatment and six months later. In a related
finding, Swedish researchers found those with high homocysteinemia
blood levels were more than twice as likely to have depression.
Homocyteine is an amino acid involved in 1-carbon metabolism,
along with folate and vitamin B12.
Meanwhile, a Stanley Medical Research Institute
study of 59 depressed bipolar patients found that those on 6 g/day
EPA, one of the active ingredients in omega-3, did no better than
those taking the placebo over four months.
Poison-ality
In May this year, this writer asked readers to
take a Myers-Briggs personality test. Of the first 100 responses
analyzed, a mind-boggling 83 turned out to be introverts (as
opposed to 25 percent to be found in the general population).
Disproportionate numbers were "mystics" and "dreamers" and
"visionaries," further reinforcing the loner profile. Whether
personality feeds on illness or vice-versa remains to be seen, but
clearly we are saddled with a monumental double-whammy that
psychiatry needs to be addressing.
The Budget Axe
Depressingly - despite all the encouraging
research advances this year - mental health services in the US
continued to deteriorate in the face of a severe budget crunch,
with services cut, staff laid off, meds denied, and facilities
closed by cash-strapped cities, counties, and states. State and
local budgets will still be swimming in red ink in 2004,
regardless of any economic recovery, which made the release of the
President’s Freedom Commission Report on Mental Health this year
something of a cruel joke.
The Silver Screen
Nicole Kidman won an Oscar for her portrayal of
Virginia Woolf in "The Hours," but "Sylvia," based on the life of
Sylvia Plath and starring Gwyneth Paltrow had only a limited run
in select theaters before dropping off the map. Meanwhile, "Prozac
Nation," the Christine Ricci vehicle which had a showing at the
2001 Toronto Film Festival, is collecting dust in a Miramax vault.
Next year and beyond? Spiderman Tobey McGuire as "Electroboy,"
based on Andy Behrman’s memoir of mania, seems likely, while Kay
Jamison’s "An Unquiet Mind" is in development.
Segue
That was the year that was. And now back to
normal programming ...
Cymbalta
An Eli Lilly
study of 1279 depressed patients has found 50.8 percent of
those on 80 to 120 mg/day of Cymbalta remitted by week six. At
week 28, the remission rate was 75.6 percent and at 52 weeks was
81.8 percent. Cymbalta is a dual-action antidepressant
FDA-approved for treating depression, but not cleared for
marketing until Eli Lilly resolves manufacturing quality control
issues, anticipated in 2004.
Juiced Up
A USDA Human Nutrition Research Center on
Aging/Welch Foods
study of rats nearing the end of their expected life spans has
found that feeding them Concord grape juice "appeared to reduce or
reverse the loss of sensitivity of muscarinic receptors, thus
enhancing cognitive and some motor skills." Juice-fed rats
negotiated a water maze in 20 percent less time than the controls,
among other tasks. Similar effects have been found in blueberries.
Concord grape juice has the highest antioxidants of any fruits,
vegetables, or juices.
Ritalin Depression Link
A Harvard
study of rats on Ritalin has found that exposure at an early
age resulted in depression and other behavior changes that endured
into adulthood.
Kids
A University of Pennsylvania
survey of 3,955 children has found that the seven percent of
the population with behavior disorders incurred double the
expenses of healthy kids with common chronic disorders such as
asthma, epilepsy, or diabetes ($1,468 vs $710 per patient) and
more than youngsters with physical disorders ($1,071).
Bipolar Kids
A Texas Community Mental Health
re-evaluation (using both standard and modified criteria for
mania) of 104 prepubertal children presenting with ADHD found that
62 had a mood disorder, "especially unrecognized bipolarity,"
leading the authors of the study to conclude: "We suggest that
clinicians encountering children with prominent features of ADHD
inquire about grandiosity and flight of ideas."
Meditation
"If you're feeling better at the end, you are
probably doing it right." Roger Thomson, PhD, a Chicago
psychologist and Zen meditator on mediation, quoted in an article
in
Psychology Today.
Heart and Soul
Two heart studies:
A Duke University
study of 280 coronary bypass patients has found that women’s
quality of life improved less than men's following the procedure,
and they had higher levels of depression and anxiety. A possible
answer for the discrepancy was nearly half the women in the study
lived alone vs 85 percent of the men who were married (and thus
had their wives caring for them).
A Behavioral Medicine Center (St. Louis)
study of 766 recovering heart patients over 30 months found
those with major or minor depression were at 2.4 times greater
risk of dying from heart attack.
Psychiatric Protection Orders
A thought-provoking article in the
British Medical Journal by Thomas Szasz MD (forget for the
time being that he thinks mental illness is the creation of the
psychiatric establishment) argues the case for "psychiatric
protection orders" that would safeguard patients from involuntary
treatment and make it a criminal offence to impose involuntary
psychiatric interventions.
Silver Ribbon Stamp
During the week of January 22, 2004, the US
Postal Service's Citizens Stamp Advisory Committee will consider a
long-standing proposal for a first class "Silver Ribbon" Brain
Disability Awareness postage stamp to help eliminate stigma and
discrimination surrounding mental illnesses. You can express your
support at:
http://usps.custhelp.com/cgi-bin/usps.cfg/php/enduser/ask.php
Oops
Last week’s Newsletter made a reference to a
Charles Krauthammer column without supplying the link to that
column. Mission accomplished.
Mailbag
Newsletter 5#30 reported on a professor who
joked to a psychology class on people with bipolar believing they
are God. Francine writes:
I found the story about Nicole’s professor very
perturbing. I am bipolar (mixed) and have never thought I was God.
I find it irritating that a professor would make such a blanket
statement to a class and not even qualify it with the varying
classes and degrees of the illness. It just makes me want to
wretch when people in an authoritative position, especially in the
educational field, make such jokes at the expense of those of us
who would give our right arm (or maybe all limbs) not to have to
be bipolar anymore.
Happy Holidays
To all of my readers, many thanks for your
support and encouragement throughout 2003, and a happy and safe
holidays to all of you. See you in 2004.
McMan's Web
Check out more than 250 articles on all aspects of depression
and bipolar, plus a bookstore, readers' forum, message boards, and
other features at:
http://www.mcmanweb.com
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