The localization of substance P in brain regions that coordinate stress
responses and receive convergent monoaminergic innervation suggested
that substance P antagonists might have psychotherapeutic properties.
Like clinically used antidepressant and anxiolytic drugs, substance P
antagonists suppressed isolation-induced vocalizations in guinea
pigs. In a placebo-controlled trial in patients with moderate to
severe major depression, robust antidepressant effects of the
substance P antagonist MK-869 were
consistently observed. In preclinical studies, substance P
antagonists did not interact with monoamine systems in the manner
seen with established antidepressant drugs. These findings suggest
that substance P may play an important role in psychiatric disorders.
M. S. Kramer is at Merck Research Laboratories, West Point, PA 19456, USA,
and in the Department of Psychiatry and Human Behavior, Thomas Jefferson Medical
College, Philadelphia, PA 19107, USA. N. Cutler and J. J. Sramek
are at California Clinical Trials, Beverly Hills, CA 90211, USA. J. Feighner
is at the Feighner Research Institute, San Diego, CA 92121, USA. R. Shrivastava
is at the Eastside Medical Group, New York, NY 10021, USA. J. Carman
is at Carman Research, Smyrna, GA 30080, USA. S. A. Reines, G. Liu,
D. Snavely, and E. Wyatt-Knowles are at Merck Research Laboratories,
West Point, PA 19456, USA. J. J. Hale, S. G. Mills, M. MacCoss,
M. A. Cascieri, G. G. Chicchi, and S. Sadowski are at
Merck Research Laboratories, Rahway, NJ 07065, USA. C. J. Swain,
T. Harrison, R. G. Hill, F. Hefti, A. R. Williams,
L. Hewson, D. Smith, E. J. Carlson, R. J. Hargreaves,
and N. M. J. Rupniak are at the Merck Sharp & Dohme
Neuroscience Research Centre, Harlow CM20 2QR, England. E. M. Scolnick
is at Merck Research Laboratories, West Point, PA 19456, USA, and Merck
Research Laboratories, Rahway, NJ 07065, USA.
M. Kramer and N. Rupniak are the principal contributors to the clinical and
preclinical studies, respectively
September 11, 1998
Web posted at: 5:43 p.m. EDT (1743 GMT)
WASHINGTON (AP) -- Scientists
may have stumbled onto an entirely
new way to treat depression: an
experimental drug that targets a
mysterious brain chemical that until
now, doctors did not know was at
work in mental disorders.
Merck & Co.'s new drug, the subject of an account published Friday in the
journal Science, works on a chemical pathway that differs from every
antidepressant sold today and offers hope to patients who get no help from
standard therapies.
"This is really very important," said Dr. Steven Hyman, director of the
government's National Institute of Mental Health, who is familiar with the
findings. "To everybody's surprise, it (the new drug) was robustly effective
for depression."
Encouraged by the first positive results in human testing, Merck is rapidly
planning the large-scale Phase III studies required before its new drug would
be eligible to sell.
Depression is the nation's most prevalent mental health problem, affecting
about 15 million Americans at some point in their lives. Americans spend
about $3 billion a year on drugs to battle it. Those drugs do help many
patients, but they can cause serious side effects.
Also, some 20 percent of patients get no help from today's medicines, which
all target either serotonin or norepinephrine, brain chemicals called
neurotransmitters, Hyman said. So scientists have long hunted another way
to attack depression.
Merck says its new drug, code-named MK-869, may do just that, by
targeting a brain chemical called substance P.
In a study of 213 patients with moderate to severe depression, Merck tested
MK-869 against Paxil, a popular and effective antidepressant, or against a
placebo. During the six-week study, MK-869 relieved depression as
effectively as Paxil did, but with fewer side effects, Merck lead researcher
Dr. Mark Kramer reported in Science.
Just how MK-869 worked inside these patients' brains remains a mystery
that has doctors intrigued -- because nobody knows just how substance P
would affect depression. In fact, nobody knew it did until Merck showed
that blocking substance P with its new drug helped patients.
"The idea of a whole new neurochemical system that might be in hyperdrive
... is a really exciting thing, and offers a new window for understanding"
depression, Kramer explained.
Substance P is a neuropeptide, a small protein that helps nerve cells
communicate.
Merck designed a chemical that blocks substance P. In animal testing,
company scientists proved that blocking substance P did not affect the
function of serotonin or norepinephrine, the two brain chemicals that today's
antidepressants target. Clearly, it was relieving psychological symptoms in an
entirely new way, so they tried MK-869 in people.
The experimental drug helped significantly improve depression in about half
of patients tested, about the same number that Paxil helped. But MK-869
patients reported far fewer cases of sexual dysfunction, a common side
effect of antidepressants.
Why would it work? A hint is that one part of the brain behind the ears that's
important in regulating negative emotions "is literally packed with substance
P receptors," said Hyman of the National Institute of Mental Health.
Hyman said Merck should quickly study patients who have failed standard
antidepressants to see if MK-869 will offer the help they desperately need.
He cautions that scientists must verify Merck's findings to be sure that
blocking substance P really works.
"Drug Appears To Fight Depression"
By Lauran Neergaard
The Associated Press
WASHINGTON (Sept. 10) - An experimental drug appears to alleviate
depression by blocking a mysterious brain chemical -- one that until now,
doctors didn't even know was at work in mental disorders.
The finding by Merck & Co., published in Friday's edition of the journal
"Science", could give doctors the first entirely new way to treat
depression in decades, offering hope to patients who get no help from
today's therapies such as Paxil and Prozac.
"This is really very important", said Dr. Steven Hyman, director of the
government's National Institute on Mental Health, who is familiar with
the findings. "To everybody's surprise, it (the new drug) was robustly
effective for depression."
The drug still needs more extensive testing in humans, however, before it
would be eligible to receive government approval to be sold.
Depression is the nation's most prevalent mental health problem,
afflicting about 15 million Americans at some point in their lives.
Americans spend about $3 billion a year on drugs to battle it. Those
drugs do help many patients.
But they also can cause serious side effects. Also, some 20 percent of
patients get no help from today's medicines, which all target serotonin,
norepinephrine, or dopamine -- brain chemicals called neurotransmitters,
Hyman said. So scientists have long hunted another way to attack
depression.
Merck says its new drug, code-named MK-869, may do just that, by
targeting a brain chemical called Substance P that until now has been a
mystery.
In a study of 213 patients with moderate to severe depression, Merck
tested MK-869 against Paxil, a popular and effective antidepressant, or
against a placebo. During the six-week study, MK-869 relieved depression
as effectively as Paxil did, but with fewer side effects, Merck lead
researcher Dr. Mark Kramer reported in "Science".
Just how MK-869 worked inside these patients' brains remains a mystery
that has doctors intrigued.
Substance P is a neuropeptide, a small protein that helps nerve cells
communicate. It was discovered in 1931, and doctors theorized it might
offer a way of treating chronic pain when they learned it played some
role in alerting nerve cells to tissue damage. Instead, "it's been a
disappointment", Hyman said -- the chronic pain research has failed.
Merck scientists theorized that substance P was playing a role in
"emotional pain", based on how animals put in stressful situations to
mimic human psychological stress reacted to higher or lower levels of the
neuropeptide.
Merck designed a chemical that blocks Substance P. In animal testing,
company scientists proved that blocking Substance P did not affect the
function of serotonin or norepinephrine. Clearly, it was relieving
psychological symptoms in an entirely new way, so they moved to testing
MK-869 in people.
Based on standard psychological test scores, the experimental drug helped
significantly improve depression in about half of patients tested, about
the same number that Paxil helped.
MK-869 appeared to have fewer side effects. Some 29 percent of Paxil
patients reported sexual dysfunction, a common antidepressant side
effect, versus just 3 percent of MK-869 patients. MK-869 patients also
reported slightly less nausea, and fewer patients dropped off the
medication because of side effects than did Paxil patients.
Why would it work? Scientists don't quite know, but a hint is that the
part of the brain behind the ears that's important in regulating negative
emotions "is literally packed with Substance P receptors", the
government's Hyman said.
Merck said it is planning Phase III trials of the drug -- the much-larger
human studies that the Food and Drug Administration requires for ultimate
proof of whether a new drug works.
Hyman said the company should quickly study patients who have failed
standard antidepressants to see if MK-869 will offer the help they
desperately need -- and he cautions that scientists must verify Merck's
findings to be sure that blocking Substance P really helps.
Substance
P
Will it prove to be the key to emotional health?
|
|
Roy Palmer, Ph.D.
The Daily Apple
|
Recently published research has created a buzz of
excitement in the world of neuroscience and psychiatry. It revolves around a
chemical with the cryptic name of Substance P.
Since Substance P was first discovered in 1931 it has been
somewhat of a mystery in terms of its precise role. The researchers who
extracted chemical from the brains and gastrointestinal tracts of horses
purified the substance into a powder which was the source of the "P"
in its name.
Since then, scientists have found Substance P concentrated
in many areas of the brains, spines and nerves of laboratory animals.
What does
the research show?
Much recent research has been done on Substance P and
there has been speculation that it may be involved in many disease states
including chronic pain, migraine headaches, asthma, inflammatory bowel disease
and perhaps insomnia. The key to clarification of the role of Substance P in
disease was the development of a drug that could block its action. Over the last
few years several drugs that block the action of Substance P have been evaluated
in various clinical conditions: pain, migraine, and asthma. However, the drugs
have failed to work in these conditions.
An estimated 20% of the nation's 17 million people
suffering from depression aren't helped by the current treatments such as
Prozac, Paxil and Zoloft. Substance P is one of several dozen brain chemicals,
or neurotransmitters, that relay signals between brain cells. Today's
top-selling antidepressants work largely by targeting the neurotransmitter
serotonin, which is at lower-than-normal levels in the brains of many depressed
people. These popular drugs, "serotonin reuptake inhibitors," boost
serotonin levels in key parts of the brain. In fact, all the established
treatments for depression are believed to work in essentially the same way by
increasing the levels of serotonin and related monoamine molecules in the brain.
Scientists at a pharmaceutical company speculated that
Substance P may play a role in the regulation of mood and anxiety. They did
animal experiments that were consistent with this speculation. They then did a
trial comparing MK-869 (the Substance P blocker they have developed) with Paxil,
a Prozac-style antidepressant, and with a placebo. The test, involving three
groups of patients totaling 210 people, yielded more significant results than
anyone had anticipated. Depressed patients who received MK-869 for six weeks
experienced at least as much relief as those who received the standard drug --
but with significantly fewer side-effects.
Hope
for the future
Substance P drugs could lead to an entirely new category
of antidepressants that could bring relief to the patients in whom traditional
antidepressants are not effective. Substance P drugs could be an important
breakthrough for the millions more patients who suffer side effects such as
reduced sexual desire, heightened anxiety and insomnia from existing depression
drugs to such an extent that they eventually stop taking them.
The large-scale tests to confirm the promise of Substance
P drugs are expected to take at least two years before the drugs will be
available to be prescribed.
The results of the studies which were published in the
prestigious scientific journal Science have sparked tremendous interest
among neuroscientists and psychiatrists. There are many questions to be answered
and numerous companies are believed now to be working on Substance P
antagonists. It may indeed turn out that Substance P is a key regulator of mood
and anxiety and that medications that block its action will be a breakthrough
for patients.
New class of antidepressants show promise
September 11, 1998
NEW YORK (Reuters) -- A new approach to antidepressant therapy
shows promise for patients who have major depressive disorder and anxiety,
according to a report in the September 11th issue of the journal Science.
Dr. Nadia M.J. Rupniak, of the Merck Sharp & Dohme Neuroscience
Research Centre in Harlow, England, and associates describe a new class of
antidepressants that counteract the effects of substance P, a brain chemical
that is thought to have a role in mood disorders.
"This represents a breakthrough in that it's a different
approach to the treatment of depression," Rupniak told Reuters Health. "It's
also a basic research breakthrough in helping us understand how the brain
works and how it may become dysfunctional in mental illness."
Rupniak and colleagues studied substance P antagonists in both
animals and humans. In one experiment, they treated guinea pig pups with one
of two substance P antagonists or with a commercially available
antidepressant or anti-anxiety drug. Thirty minutes to 4 hours later, the
researchers separated the pups from their mothers for 15 minutes.
Similar to pups that received the proven drugs, pups that
received the substance P antagonists did not make distress calls, the
research team reports. The team infers from this finding that substance P
antagonism "is capable of inhibiting behavioral responses to psychological
stress."
Investigators at four sites then conducted a clinical trial of
MK-869, a long-acting substance P antagonist that is taken orally. Rupniak's
team randomly assigned 213 patients with major depression and moderately
high anxiety to take either 300 milligrams (mg) of MK-869, 20 mg of
paroxetine, or a placebo (inactive pill), once daily for 6 weeks.
The efficacy of MK-869 was similar to that of paroxetine in
regard to all outcomes measured, the investigators observed. Patients who
received MK-869 improved by an average of 4.3 points on a questionnaire
about symptoms of depression, and 54% improved by 50% or more.
"MK-869 also demonstrated significant (anti-anxiety) activity in
this population," the authors write. They suggest that the anti-anxiety
effect of the drug may be independent of its antidepressant effect.
In general, the side effects of MK-869 were mild and were
similar to those of paroxetine, Rupniak's group found. Compared with
patients taking paroxetine, patients taking MK-869 were significantly less
likely to experience loss of libido, ejaculation disorder, or impotence.
"The substance P antagonists, so far as we're able to tell, act
in a very different way from the currently available antidepressant drugs."
Rupniak said in the interview with Reuters Health.
"So this is not just another new antidepressant," she continued.
"It's actually a new mechanism of action, and as such, we believe that the
side effect profile and the tolerability of these compounds is going to be
significantly different than that of the available drugs."
"This study offers hope for depressed patients who experience
incomplete efficacy or distressing adverse effects when treated with
currently available drugs," Dr. Claes Wahlestedt, of the Karolinska
Institute in Stockholm, Sweden, agrees in an editorial.
SOURCE: Science 1998;281:1624-1625, 1640-1645.
by Kenneth J. Bender, Pharm.D., M.A.
Psychiatric Times November 1998 Vol.
XV Issue 11
An investigational compound that blocks the neurokinin "substance P"
has demonstrated robust antidepressant effect in preliminary clinical testing
against paroxetine (Paxil) and placebo. For several years, Merck & Co.
researchers have been searching for such a compound useful for the migraine or
general pain conditions suggested by substance P distribution in the nervous
system. This finding has been described by Edward Scolnick, M.D., president of
Merck Research Laboratories, as "a breakthrough discovery" in mental
health care.
Experts outside Merck Research have concurred that this is an important
discovery. James Krause, Ph.D., vice-president of Neurogen Corp., told Wall
Street Journal reporter Robert Langreth, "The Merck finding will
stimulate a whole new avenue of research into understanding the biology of
depression."
Steven Hyman, M.D., director of the National Institute of Mental Health (NIMH),
found the results of the phase II trial "an extraordinary surprise."
If the findings hold up in subsequent, larger phase III trials, "it gives
researchers a whole new target for developing depression treatments," Hyman
said.
In the Sept. 11 issue of Science, Mark Kramer, M.D., senior research
physician at Merck, Nadia Rupniak, Ph.D., senior research fellow at Merck in the
United Kingdom, and colleagues reported preclinical indications that substance P
antagonists affect stress response and emotion. They rapidly progressed to a
phase II clinical test in patients with depression (Kramer et al.,1998).
The randomized double-blind, placebo-controlled study comprised 210 patients
with major depressive disorder and "moderately high" anxiety. Subjects
given single 300 mg daily doses of the agent, designated MK-869, and 20 mg of
paroxetine produced similar reductions in total Hamilton Depression Rating Scale
(HAM-D-21) scores from baseline to week 6 that were significantly superior to
placebo response.
The substance P neuropeptide was first identified by Swedish researchers in
1931. It has been investigated extensively since 1970, when its chemical
structure was characterized and a synthesized form became available. Its
function has remained elusive.
"Substance P was considered a neurotransmitter in search of a
disease," was the comment made to Langreth by Alan Metz, M.D., director of
medical affairs for the central nervous system (CNS) section of Glaxo Wellcome,
where substance P antagonists have been investigated for possible benefit in
nausea and other conditions.
Kramer is credited for positing that substance P might be more closely linked
to "psychic pain" than to the previously investigated headache or
general pain. He noted that while substance P has been determined to be the most
abundant neurokinin in the mammalian CNS, it is particularly concentrated in the
amygdala and other regions thought critical for regulation of affective behavior
and neurochemical responses to stress.
His hypothesis was taken up by Rupniak, whose group subjected the neurokinin
and two antagonists to a series of preclinical evaluations of their effects on
stress and emotion. In common with traditional anxiolytic and antidepressant
medications, the substance P antagonists were found to inhibit stress-induced
vocalizations in guinea pigs. In one of several studies they conducted, the
substance P antagonists were comparable to these traditional medications in
reducing vocalizations in guinea pig pups separated from their mother and
littermates. The audible cries they made in this circumstance were similar to
those evoked by central infusion of substance P.
The investigators reported, "These studies demonstrate that selective
pharmacological blockade of substance P receptors is capable of inhibiting
behavioral responses to psychological stress in a manner resembling the effect
of clinically used psychotherapeutic agents."
Subsequent studies by this group have shown that substance P antagonists do
not act by augmenting norepinephrine or serotonin in a manner occurring with
established antidepressants; but a mechanism of action remains to be elucidated.
The investigators indicate only that the atypical profile emerging from their
evaluations, "supports the proposal that the antidepressant activity of
substance P antagonists is mediated via a novel mechanism."
Although mechanisms of action remain unknown, the investigators suspect that
the amygdala is a principal site of action, not only for MK-869, but for
traditional antidepressants as well. They note that focal injection of the
tricyclic antidepressant imipramine (Tofranil) into the amygdala has produced
similar responses in psychological stress evaluations as those produced after
systemic administration. A major output projection from the amygdala is to the
hypothalamus, and the investigators have demonstrated that electrical
stimulation of the amygdala produces the same defensive rage syndrome in cats as
direct stimulation of the hypothalamus. They hypothesize that substance P
enhancement of transmission from the medial amygdala to the hypothalamus
mediates emotional response to stress.
Alleviating Pain of Depression
The substance P antagonist MK-869 was developed to be orally bioavailable
with good CNS penetration and receptor specificity, and is sufficiently
long-acting for single daily dosing. In the 6-week evaluation of its safety and
efficacy in humans, the HAM-D-21 was applied at weeks 1, 2, 4 and 6 as the
primary measure of efficacy. An antidepressant effect of MK-869 was apparent at
all intervals, and was corroborated by Clinical Global Impression Severity Scale
ratings.
Fifty-four percent of patients receiving MK-869 achieved a 50% or greater
reduction in baseline HAM-D score by week 6, compared to 43% of those receiving
paroxetine and 28% with placebo. Further, 43% of the patients receiving MK-869
achieved HAM-D scores below 10, which the investigators regarded as a
"complete" response, compared to 33% of those on paroxetine and 17% of
patients receiving placebo. The anxiolytic effects of the active drugs, assessed
with the Hamilton Anxiety Scale, were similar through week 4, with somewhat
greater effect evidenced with paroxetine by week 6.
Differences in specific HAM-D item results were assessed to further
distinguish the active agents. Patients receiving MK-869 had more improvement
with insomnia than did patients on paroxetine, while those receiving paroxetine
demonstrated greater improved insight.
The investigators characterized the adverse effects from MK-869 as
"generally similar to placebo," except for somnolence and asthenia,
which occurred with both active agents and were described as "mild and
typically transient." There were notably fewer patients experiencing sexual
dysfunction with MK-869 (3% compared to 4% on placebo) than the 26% of patients
receiving paroxetine.
Adverse effects prompted 19% of those receiving paroxetine to discontinue
treatment, compared to 9% of those on MK-869 and 9% of those on placebo. Nausea,
occurring in 29% of patients receiving paroxetine compared to 10% of those
receiving MK-869, was the principal cause for patients discontinuing treatment
with paroxetine. No specific side effect emerged as a principal cause for
discontinuing either MK-869 or placebo. Treatment with MK-869 was not associated
with drug-seeking behavior, or clinically significant changes in physical
examination findings, including vital signs, weight or heart rate (measured by
electrocardiogram).
NIMH director Hyman has urged the researchers to go forward in their clinical
testing to include patients who have not improved on traditional
antidepressants, and Kramer commented that he is excited about the therapeutic
potential of this product. "We are dealing with a new system that is
probably closer to the source of depression," he said.
Reference
Kramer MS, Cutler N, Feighner J et al. (1998), Distinct mechanism for
antidepressant activity by blockade of central substance P receptors. Science
281:1640-1645.
NEW CLASS OF DRUGS
Blocking Neurokinin-1 (NK-1) Receptor
Showing possible promise is a totally new class of antidepressants, those
that block the neurokinin-I (NK-l) receptor/Substance-P/ NK-l antagonists were
initially studied for pain control or as relief for anxiety and now are being
researched for depression.
http://www.carcinoid.org/FAQSUM.htm
(Potential substance P blood test? info there) expanded from the differential
diagnosis page.
?
What is Neurokinin B and it’s relationship to Carcinoid/Syndrome?
A
Neurokinin B is a nonspecific peptide hormonal substance sometimes
co-secreted into the blood along with one of the other carcinoid products such
as serotonin, chromogranin A, substance P and pancreatic polypeptide
---
>How does a person persuade Merck to include them in their testing of this
>new drug? I very much wish to try it out. I feel it is urgent to do so. Hi
Robert. I've been thinking of the same thing, actually. Probably the best thing
to do would be have your psychiatrist call Merck (800 672 6372) and inquire
about sites where the phase III testing is going on. A caution about these
clinical trials: for the period of the trial (usually about 6 weeks) you may be
getting placebo - you won't find out until the trial is over. Also, they tend to
not want you to be on other medications at the same time (this is not absolute),
and there is no guarantee that they would let you keep taking the drug after the
trial finished (although I'd think they would be psyched to do so if it helped
you - looks good for them if people want to keep taking it). Have your doctor
find out about the specific protocols for any trials you are considering
participating in. Good luck!
