Drug Makers' Goal: Benefits Of Prozac -- Without the Lag
April 27, 1998
By THOMAS M. BURTON
Staff Reporter of THE WALL STREET JOURNAL
The drug industry is in a high-stakes race to produce a
faster-acting remedy for depression.
Few products in recent medical history have had as big
an impact as the leading antidepressant, Prozac, and its
top competitors, Zoloft and Paxil. Together the three
drugs account for sales of more than $5.5 billion a year
and are improving the lives of millions of patients.
But there's a big catch: The medications typically take
two to six weeks -- or even longer -- to really work.
That can be a lifetime for someone with severe
depression, particularly now that insurance restrictions
make it more difficult than ever to hospitalize long-term
mental-illness patients.
As a result, finding a quicker cure "has been one of the
Holy Grails of psychiatry," says Andrew A. Nierenberg,
associate director of the depression program at
Massachusetts General Hospital.
Leading the quest are Prozac's maker, Eli Lilly & Co.;
Pfizer Inc., which makes Zoloft, and SmithKline
Beecham PLC, Paxil's supplier. Other major players
include Bristol-Myers Squibb Co., which makes another
competing drug, Serzone; Glaxo-Wellcome PLC,
makers of the antidepressant Wellbutrin; Johnson &
Johnson and Boehringer Ingelheim AG.
The most intensive research focuses on one curious
aspect of the human brain's physiology: Its tendency to
resist the biochemical effects of most of the current
top-selling drugs for the first few weeks.
Prozac, Zoloft and Paxil all act by increasing the amount
of the chemical serotonin in the brain. Serotonin is a
neurotransmitter, a chemical messenger that helps brain
cells, called neurons, send information to each other.
Higher levels of serotonin are crucial to better moods.
Tiny points called receptors on each brain cell are the
brain-cell components that "talk" to each other through
the serotonin. But certain receptors, called the 1A and
1D receptors, become desensitized to serotonin
immediately after there is a sharp increase in the brain's
serotonin level.
This inhibits the antidepressants' mood -- improving
activity from getting started for several weeks. "It's as if
there's a foot on the accelerator and another one on the
brake, so the net effect is the car isn't moving too fast,"
says Lilly's Steven M. Paul, vice president of discovery
research.
Finding a drug to take the foot off the brake "is where
the big action is now," says Perry Molinoff, vice
president of neuroscience drug discovery at
Bristol-Myers. All the major research players are
focusing on this approach, among others.
Intense and animated, the 47-year-old Dr. Paul worked
under Nobel laureate Julius Axelrod at the National
Institute of Mental Health. Scientists working under him
have identified at least three compounds that, in
laboratory rats, quickly produce the higher serotonin
levels or other biochemical effects believed to relieve
depression, though the company declines to specify how
they work. Dr. Paul says he expects human clinical
studies on various companies' drugs to be nearly
complete within two to four years.
Bristol-Myers has also isolated chemicals that seem to
be faster-acting and more effective. Improving the
efficacy is also important, because about 25% of
depressed patients don't seem to respond to any drug,
and many others respond only partially.
Heading the Bristol-Myers effort is Arlene Eison, 44, the
company's principal scientist in neuroscience drug
discovery. She originally became interested in
mental-health drugs when she was a high school student
working with autistic children at Camarillo State Hospital
in California. At Bristol-Myers, her work on two
serotonin-based drugs -- the antidepressant Serzone and
the anxiety drug Buspar -- led to the current research.
One approach at Bristol-Myers is to find which one or
more of the 15 known serotonin receptors on each brain
cell play the biggest roles in depression. "Nobody knows
which of the serotonin receptors is being activated," says
Dr. Molinoff. "If we home in on the specific receptor,
we'll automatically have a faster acting and more
efficacious compound."
Pfizer, too, has found some apparently quicker-acting
compounds. Later this year, at least one will likely be in
human clinical testing, says James Heym, Pfizer's group
director of neuroscience and general pharmacology. The
47-year-old Dr. Heim was a serotonin researcher at
Princeton University before joining Pfizer at its Groton,
Conn., labs 15 years ago. At the company, he was an
early project manager on Zeldox, a schizophrenia drug
Pfizer hopes to market soon.
Pfizer is also exploring the possible involvement in
depression of entirely different brain chemicals, called
neuropeptides. These are chains of amino acids that can
also serve as chemical messengers between cells.
One such chemical, called CRH, or
corticotrophin-releasing-hormone, is found at relatively
higher levels among depression patients and suicide
victims. Pfizer, among other companies, is searching for
a drug that would limit the effects of CRH on brain-cell
receptors -- and maybe quickly uplift patients' moods
because there might not be any built-in braking
response.
SmithKline is moving into late-stage human clinical
studies of a drug combination made up of its Paxil and a
generic cardiac drug called pindolol. In Spain and
Canada, scientists have used pindolol in combination
with Prozac and Paxil to turbocharge the
antidepressants. Research on the combination elsewhere
has produced mixed results, but both SmithKline and
Lilly are moving forward with the combined-drug
approach.
Pindolol, aside from being a long established cardiac
drug, also happens to be a drug that is an "antagonist" of
the 1A receptor that acts as a brake on the effects of
serotonin. In effect, it's a brake on the brake. But
because it's a cardiac drug, pindolol also lowers blood
pressure and the heart rate and may be far from an ideal
solution.
Along with the drug companies, various psychiatrists are
experimenting on their own. Some get quicker results for
certain patients by combining the new drugs with older
antidepressants called tricyclics simultaneously.
American Home Products Co.'s new antidepressant,
Effexor, may relieve depression in the first week in
certain patients if they can tolerate very high doses of the
drug, company scientists report.
For many other patients, electro-shock treatment is the
only fast-acting option. And oddly, depriving a patient of
approximately one night's sleep sometimes has amazingly
quick effects in countering a severe depressive episode.
"Nobody knows why it works," says Lilly's Dr. Paul.
"But it does suggest to us that a quick response is
possible."
Some technical obstacles make companies' new-drug
research particularly difficult. One is the fact that
scientists haven't yet been able to design a depressed lab
rat genetically. Thus, while researchers can measure
serotonin levels in rats' brains, they can't truly measure a
drug's behavioral effects on the rats. "We wouldn't
recognize a depressed rat if we saw one," says Lilly's
Chris Fibiger, vice president of neuroscience research
and discovery.
Some researchers also hope to be able to use high-tech
"imaging" of depressed human patients' brains to actually
see if new compounds are changing brain chemistry.
Right now, this technology isn't advanced enough. But
Harvard Medical School researcher Darin Dougherty
says he expects that imaging will soon play a significant
role in exploring faster antidepressants. |
