Next Generation of Psychiatric Drugs Will Be Quicker and Safer

All the following information is courtesy of DJ Jaffe (AMI/FAMI NYC):

Move over Prozac, Xanax and all the other balms for the distressed in
current vogue: scientists are heralding a new generation of designer drugs,
psychiatric medications more powerful, quicker acting and with fewer
unwanted effects.

A handful of the new medications are undergoing the first phase of tests
in patients and should reach the market within the next five years; others
are merely glimmers in the eyes of psychopharmacologists.

All are possible because of recent advances in neuroscience research, the
fruit of the much vaunted "Decade of the Brain," a concentrated initiative
by the National Institute of Mental Health to push back the frontiers of
basic knowledge about the workings of that miraculous, mysterious bundle of
billions of neurons.

Neuroscience is poised to create "new medications both more effective and
with fewer side effects than any before, by taking advantage of a wave of
breakthroughs," said Dr. Steven Hyman, director of the National Institute of
Mental Health.

Foremost among these breakthroughs is a startling revelation about brain
cells. Until recently neuroscientists had thought there were just one or two
variations of each type of receptor, the proteins in and on brain cells that
receive chemical messages. Those messages dictate what a brain cell does, and
the result may be the weight of sorrow or a surge of delight. Now scientists
realize there may be as many as a hundred or more variations of a given
receptor protein.

Fifteen different receptors have been found for serotonin, a
neurotransmitter involved in depression; five for dopamine, implicated in
symptoms of schizophrenia; six kinds for norepinephrine and possibly dozens
for GABA, both of which play roles in anxiety disorders and depression.

Estimates for glutamate receptors, found on every neuron, run as high as a
hundred or more uniquely differing receptors that control aspects of
essential functions like learning and memory. Each of these receptors
controls functions as different as mood, the coordination of movements,
sexual interest and digestion.

Current psychiatric medications lessen or increase activity at all the
receptors for a given neurotransmitter like serotonin indiscriminately, and
so cause side effects like stomach problems. The next breed of drugs will
target just the specific receptor that controls the symptom in question,
scientists say, and so will offer greater potency with fewer side effectss.

The greatest enthusiasm, understandably, comes from neuroscientists at
pharmaceutical companies. "The coming generation of psychiatric medications
will be 10 times better than those we have now," said Dr. Steven M. Paul, one
of those at the forefront of the development of the coming breed of
psychiatric medications. Now head of neuroscience research at Eli Lilly & Co.
in Indianapolis, Dr. Paul was, until he joined Lilly in 1993, the scientific
director of intramural research at the National Institute of Mental Health.

"Psychiatric medications in the next century will be totally novel in how
they work, much, much superior to any we have today," said Dr. James Heym,
director of neuroscience research at Pfizer Central Research, in Groton,
Conn., and formerly a professor of psychiatry at Yale.

But others are more cautious. Dr. Hyman, the director of the mental health
agency, said: "It's not just a question of discovering new receptors, but
figuring out what circuits they connect with, and what behavior those
circuits regulate. There's lots of basic research to do before we can best
use these discoveries to yield new medications. We have to integrate
everything from molecular biology and genetics to the study of people's

Even so, the race to market is on. Several products derived from this new
approach to developing medications are close to or already undergoing the
first phase of clinical trials, tests for toxicity and side effects in

"We're betting on this strategy," said Dr. Edward Bradley, senior vice
president for clinical research at Sanofi Winthrop Inc. in Philadelphia. "We
have medications specific for serotonin receptors in phase one trials in
Europe, and will start testing them in the U.S. by the end of the year."

If the clinical trials for this coming generation are successful, these
medications should be available to patients in the United States within the
next five years.

The earliest psychiatric drugs were the result of serendipity combined
with astute clinical observations. For example, the first anti-psychotic
medication, chlorpromazine, was accidentally discovered in the 1950s, when
scientists were testing what they thought was a new antihistamine on
psychiatric patients.

The psychiatric medications in wide use today, including Prozac and other
medications like it, are for the most part hit-and-miss refinements on the
first generation of medications. But with molecular biology offering the
first precise map of receptors, new automated methods in chemistry allow
production of an array of molecules, systematically adding small pieces to
concoct huge numbers of subtly different compounds. "Then you can test to see
if any of these subtle molecular differences makes the clinical differences
you're seeking," Paul said.

This rapid-fire testing of hundreds of thousands of compounds to find any
that have a desired effect on target receptors can shrink development time
from years to months. One simple test uses a plate with 96 small wells, each
containing a radioactive tracer for a neurotransmitter that binds to the
receptor under study.

Into each well a robotic device puts a different chemical compound, and
evaluates whether that compound interferes with the ability of the
neurotransmitter to bind with the receptor. This micro-experiment can be done
at a rate that allows testing as many as several hundred thousand different
compounds in a half year, Heym of Pfizer said.

Still, this proliferation of receptors poses a tough scientific question.
"Why are there so many different receptors?" asked Dr. Richard Weinberg, a
neuroscientist at the University of North Carolina at Chapel Hill. "We don't
know yet." Discovering that serotonin has 15 receptors instead of just two or
three is a bit like having a fuse box containing 15 fuses with just two or
three labeled; the next step is to do the detective work that reveals what
circuitry all those unmarked fuses control.

Hyman, the mental health agency chief, cautions that more basic research
is needed to discover precisely what brain circuitry connects to each of the
newly revealed receptors, and what parts of emotional and mental life those
circuits control. "How the brain was designed was determined by evolution,
and we have yet to discover the whole map," Hyman said.

Even so, most neuroscientists are optimistic about the possibilities. The
problem with current medications is that they are crude in their action,
something like flooding a garden to water it. Even the most recently
introduced psychiatric medications, like the new class of anti-psychotic
drugs that include Resperidol, Olanzepine and Sertindole, "are the last of
the older generations, because they act at many sites," said Dr. John
Tallman, scientific director of Neurogen, and formerly a neuroscientist at
Yale medical school.

All current psychiatric medications are "dirty," Tallman said, because
they do not cleanly affect only one receptor. For example, medications like
Prozac reduce depression by interfering with the ability of receptors to
reabsorb the neurotransmitter serotonin, which keeps more of the chemical
active longer in the synapses between brain cells. But the current generation
of such serotonin reuptake inhibitors act on all the serotonin receptors,
which have a role in regulating functions as diverse as sexual desire, mood
and digestion -- not just the two or three that are involved in the symptoms
of depression.

"Wouldn't it be better," Hyman asked, "to target just those serotonin
receptors that regulate mood, and leave alone those for other things like
sexual activity?"

Such medications might also work more quickly. Drugs designed to increase
serotonin levels take several weeks to begin allaying symptoms because one of
the receptors they affect is actually a brake protecting against too-high
levels of the neurotransmitter. This receptor senses when serotonin levels
are on the rise, and like a rheostat on a heater, signals the neuron to slow
down its serotonin secretion.

It generally takes about three weeks for this brake to allow secretion of
the higher levels that are clinically effective. One possibility, scientists
say, is to find a compound that will block the brake's activity, so allowing
serotonin levels to climb higher from the first day a patient takes the

But even this coming generation of wonder drugs may not be the last word
in psychiatric medications. Some neuroscientists are even willing to
speculate that in a decade or two yet another generation of medications may
help people who are at a high inherited risk avoid developing psychiatric
illnesses, from depression to psychosis.

That possibility depends on the growing understanding of the complex
genetic patterns that make people most susceptible to a given mental illness,
and the potential to use genetic testing to identify people with those
patterns long before the disease begins.

In theory, but so far in theory only, medications that amount to
preventive "cocktails" could be tailored to protect against the gaps left by
genetic endowment. "The coming generation of psychiatric medications are
still Band-Aids," said Tallman. The dream, he said, is that "we'd like to be
able to prevent psychiatric disease all together."

[ Home] [News]