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Subject: BRAIN SIGNAL ID'S RESPONDERS TO FAST-ACTING ANTIDEPRESSANT
U.S. Department of Health and Human Services NATIONAL INSTITUTES OF HEALTH
NIH News National Institute of Mental Health (NIMH)
<http://www.nimh.nih.gov/> For Immediate Release: August 3, 2012
CONTACTS: Charlotte Armstrong, Jules Asher, 301-443-4536,
<e-mail:[log in to unmask]>
BRAIN SIGNAL ID'S RESPONDERS TO FAST-ACTING ANTIDEPRESSANT Biomarkers help
pinpoint mechanisms, predict outcomes - NIH studies
Scientists have discovered a biological marker that may help to identify
which depressed patients will respond to an experimental, rapid-acting
antidepressant. The brain signal, detectable by noninvasive imaging, also
holds clues to the agent's underlying mechanism, which are vital for drug
development, say National Institutes of Health researchers.
The signal is among the latest of several such markers, including factors
detectable in blood, genetic markers, and a sleep-specific brain wave,
recently uncovered by the NIH team and grantee collaborators. They
illuminate the workings of the agent, called ketamine, and may hold promise
for more personalized treatment.
"These clues help focus the search for the molecular targets of a future
generation of medications that will lift depression within hours instead of
weeks," explained Carlos Zarate, M.D., of the NIH's National Institute of
Mental Health (NIMH). "The more precisely we understand how this mechanism
works, the more narrowly treatment can be targeted to achieve rapid
antidepressant effects and avoid undesirable side effects."
Zarate, Brian Cornwell, Ph.D., and NIMH colleagues report
<http://www.ncbi.nlm.nih.gov/pubmed/22521148> on their brain imaging study
online in the journal Biological Psychiatry.
Previous research had shown that ketamine can lift symptoms of depression
within hours
<http://www.nimh.nih.gov/science-news/2010/experimental-medication-lifts-dep
ression-symptoms-in-bipolar-disorder-within-an-hour.shtml> in many patients.
But side effects hamper its use as a first-line medication. So researchers
are studying its mechanism of action in hopes of developing a safer agent
that works similarly.
Ketamine works through a different brain chemical system than conventional
antidepressants. It initially blocks a protein on brain neurons, called the
NMDA receptor, to which the chemical messenger glutamate binds. However, it
is not known if the drug's rapid antidepressant effects are a direct result
of this blockage or of downstream effects triggered by the blockage, as
suggested by animal studies
<http://www.nimh.nih.gov/science-news/2011/drug-boosts-growth-factor-to-jump
-start-rapid-antidepressant-response.shtml>.
To tease apart ketamine's workings, the NIMH team imaged depressed patients'
brain electrical activity with magnetoencephalography (MEG). They monitored
spontaneous activity while subjects were at rest, and activity evoked by
gentle stimulation of a finger, before and 6.5 hours after an infusion of
ketamine.
It was known that by blocking NMDA receptors, ketamine causes an increase in
spontaneous electrical signals, or waves, in a particular frequency range in
the brain's cortex, or outer mantle. Hours after ketamine administration --
in the timeframe in which ketamine relieves depression -- spontaneous
electrical activity in people at rest was the same whether or not the drug
lifted their depression.
Electrical activity evoked by stimulating a finger, however, was different
in the two groups. MEG imaging made it possible to monitor excitability of
the somatosensory cortex, the part of the cortex that registers sensory
stimulation. Those who responded to ketamine showed an increased response to
the finger stimulation, a greater excitability of the neurons in this part
of the cortex.
Such a change in excitability is likely to result, not from the immediate
effects of blocking the receptor, but from other processes downstream, in
the cascade of effects set in motion by NMDA blockade, say the researchers.
Evidence points to changes in another type of glutamate receptor, the AMPA
receptor,
<http://www.nimh.nih.gov/science-news/2007/faster-acting-antidepressants-clo
ser-to-becoming-a-reality.shtml> raising questions about whether the
blocking of NMDA receptors is even necessary for ketamine's antidepressant
effect. If NMDA blockade is just a trigger, then targeting AMPA receptors
may prove a more direct way to effect a lifting of depression.
A separate study of ketamine biomarkers by the NIMH group adds to evidence
<http://www.nimh.nih.gov/science-news/2010/rapid-antidepressant-works-by-boo
sting-brains-connections.shtml> that the drug may work, in part, by
strengthening neural connections
<http://www.ncbi.nlm.nih.gov/pubmed/22676966>. Thirty treatment resistant
depressed patients who received ketamine showed increased sleep-specific
slow brainwave activity (SWA) -- a marker of such strengthened synapses and
of increased synchronization of networks in the cortex. They also had higher
blood levels of a key neural growth chemical, brain-derived neurotrophic
factor (BDNF), previously linked, in animal studies, to ketamine's action.
Intriguingly, the boosts in BDNF were proportional to those in SWA only
among 13 participants whose depressions significantly lifted -- suggesting
a potential marker of successful treatment.
"Linked SWA and BDNF may represent correlates of mood improvement following
ketamine treatment," said Zarate. "These may be part of the mechanism
underlying the rapid antidepressant effects and prove useful in testing
potential new therapies that target the glutamate system."
The increases in SWA, detected via electroencephalography (EEG), were also
reflected in increased slope and amplitude of individual brainwaves --
additional indicators of neural health and adaptability.
Prior to discovery of ketamine's antidepressant effects, the only
fast-acting antidepressant therapies were sleep deprivation and
electroconvulsive therapy (ECT), both of which are also thought to work, at
least in part, by stimulating BDNF.
There is also new evidence that people with one of two common versions of
the gene that codes for BDNF respond better to ketamine - and clues about
why. The versions are created by a site in the human BDNF gene where the
genetic code differs <http://www.genome.gov/Glossary/index.cfm?id=185>
slightly across individuals. Each person inherits two copies of the gene,
one from each parent. So people can inherit one or two copies of each
version.
In June, NIMH-funded researchers reported
<http://www.ncbi.nlm.nih.gov/pubmed/22036038> that ketamine's ability to
spur the growth of neural connections and trigger antidepressant-like
behavioral responses was impaired in mice genetically engineered to express
two copies of a risk version of the human BDNF gene that is carried by about
30 percent of the population. NIMH grantees George Aghajanian M.D., and
Ronald Duman, Ph.D., of Yale University, New Haven, Conn., also discovered
atrophy in extensions of neurons and dampened electrical activity in key
cells at the front of the brain, with the risk version.
The mouse results suggested that the same site of variability in the BDNF
gene might similarly influence patients' responses to ketamine. In July,
Zarate and NIMH colleagues reported that in 62 depressed patients, this
variability in the BDNF gene accounted for 28 percent
<http://www.ncbi.nlm.nih.gov/pubmed/22771240> of difference in patients'
responsiveness to the medication. As expected, the antidepressant effect was
strongest in patients with two copies of the other, protective version,
which is carried by about 60 percent of the population.
These results strengthen the case for BDNF's pivotal role in mediating
antidepressant effects produced via the glutamate system. They also suggest
that it might be possible to improve ketamine's antidepressant effect in
risk version carriers by first giving them treatments known to enhance BDNF,
such as exercise
<http://www.nimh.nih.gov/science-news/2011/stress-defeating-effects-of-exerc
ise-traced-to-emotional-brain-circuit.shtml>, transcranial magnetic
stimulation, ECT, or conventional antidepressants.
In another recent study <http://www.ncbi.nlm.nih.gov/pubmed/22516044> by the
NIMH team and NIH collaborators, by-products of the chemical breakdown of
ketamine, detectable in blood, helped to sort out responders from
non-responders, as well as diagnosis and symptoms. This first study of its
kind pinpointed correlates of such downstream ketamine metabolites in 45
treatment resistant depressed unipolar and 22 depressed bipolar patients.
Blood levels of one metabolite were higher among bipolar non-responders,
indicating that these patients might require a lower dose of the drug for
optimal efficacy. Levels of three related metabolites were higher in bipolar
patients, with only one, of a different type, elevated in patients with
major depression. Higher levels of three metabolites of the former type were
also associated with lower scores on measures of psychotic and other side
effects, following ketamine treatment. The identification of these
downstream metabolites opens the door to possibly developing them into newer
treatments that are better tolerated than ketamine.
Ketamine also recently produced the fastest, strongest and longest-lasting
anti-suicidal intervention ever demonstrated in a controlled trial,
according to Zarate and colleagues. In a replication of an earlier study
<http://www.nimh.nih.gov/science-news/2010/experimental-medication-lifts-dep
ression-symptoms-in-bipolar-disorder-within-an-hour.shtml>, the researchers
confirmed <http://www.eurekalert.org/pub_releases/2012-05/e-kib053012.php>
that ketamine not only lifts depression, but also reduces suicidal thoughts
in bipolar patients. The effects were detectable as soon as 40 minutes after
a single infusion in 15 treatment resistant patients taking mood
stabilizers, and remained significant for at least a few days. Three fourths
of the patients responded to ketamine, with none responding to a placebo.
The results add reduced suicidal thinking to the list of potential
therapeutic benefits of targeting the brain's glutamate system.
While the research on biological markers and mechanisms holds hope for
development of more practical medications in the long term, questions remain
about whether there might be a limited role for ketamine itself in the short
term.
In a recent assessment <http://www.ncbi.nlm.nih.gov/pubmed/22705040> of the
state of the science, Zarate and American and European colleagues propose
that intravenous ketamine may prove useful for acutely suicidal patients who
receive treatment in hospital emergency rooms. It may also offer an
alternative to ECT, long considered the treatment of last resort for
treatment resistant depression, but fraught with concerns about cognitive
side effects.
However, the researchers recommend against the use of ketamine outside of a
hospital setting, citing potential cardiovascular and other risks. They note
that anesthesiologists participate in the trials at NIMH and Mount Sinai
School of Medicine, New York City which also require a 24-hour inpatient
stay following drug infusion.
Among about 163 patients who have been studied to date, the drug has been
well tolerated and seems a reasonable treatment option for most treatment
resistant depressed patients, say the researchers. Studies are under way
using nasally administered ketamine and other strategies to determine how
the rapid antidepressant affect might best be sustained.
"We are investigating ketamine in multiple ways - studying genes, gene
expression, synapses, cells, circuits, and symptoms with neuroimaging,
genetics, electrophysiological measures and other techniques," explained
Zarate. "These studies hold hope for predicting the likelihood of response
and for gaining insights into mechanisms of action."
The mission of the NIMH is to transform the understanding and treatment of
mental illnesses through basic and clinical research, paving the way for
prevention, recovery and cure. For more information, visit the NIMH website
<http://www.nimh.nih.gov/>.
About the National Institutes of Health (NIH): NIH, the nation's medical
research agency, includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. NIH is the primary federal
agency conducting and supporting basic, clinical, and translational medical
research, and is investigating the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and its programs,
visit <www.nih.gov>.
NIH...Turning Discovery into Health
-----------------------
REFERENCES:
Synaptic Potentiation Is Critical for Rapid Antidepressant Response to
Ketamine in Treatment-Resistant Major Depression. Cornwell BR, Salvadore
G, Furey M, Marquardt CA, Brutsche NE, Grillon C, Zarate CA Jr. Biol
Psychiatry. 2012 Apr 20. [Epub ahead of print] PMID: 22521148
<http://www.ncbi.nlm.nih.gov/pubmed/22521148>
Concomitant BDNF and sleep slow wave changes indicate ketamine-induced
plasticity in major depressive disorder. Duncan WC, Sarasso S, Ferrarelli
F, Selter J, Riedner BA, Hejazi NS, Yuan P, Brutsche N, Manji HK, Tononi
G, Zarate CA. Int J Neuropsychopharmacol. 2012 Jun 7:1-11. [Epub ahead of
print] PMID: 22676966 <http://www.ncbi.nlm.nih.gov/pubmed/22676966>
Relationship of Ketamine's Plasma Metabolites with Response, Diagnosis,
and Side Effects in Major Depression. Zarate CA Jr, Brutsche N, Laje G,
Luckenbaugh DA, Venkata SL, Ramamoorthy A, Moaddel R, Wainer IW. Biol
Psychiatry. 2012 Apr 18. [Epub ahead of print] PMID: 22516044
<http://www.ncbi.nlm.nih.gov/pubmed/22516044>
Replication of ketamine's antidepressant efficacy in bipolar depression: a
randomized controlled add-on trial. Zarate CA Jr, Brutsche NE, Ibrahim L,
Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA,
Liberty V, Luckenbaugh DA. Biol Psychiatry. 2012 Jun 1;71(11):939-46. Epub
2012 Jan 31.PMID: 22297150 <http://www.ncbi.nlm.nih.gov/pubmed/22297150>
Ketamine for Depression: Where Do We Go from Here? Aan Het Rot M, Zarate
CA Jr, Charney DS, Mathew SJ. Biol Psychiatry. 2012 Jun 15. [Epub ahead of
print] PMID: 22705040 <http://www.ncbi.nlm.nih.gov/pubmed/22705040>
Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Antidepressant
Efficacy of Ketamine in Depressed Patients. Laje G, Lally N, Mathews D,
Brutsche N, Chemerinski A, Akula N, Kelmendi B, Simen A, McMahon FJ,
Sanacora G, Zarate C Jr. Biol Psychiatry. 2012 Jul 5. [Epub ahead of
print] No abstract available. PMID:22771240
<http://www.ncbi.nlm.nih.gov/pubmed/22771240>
Brain-derived neurotrophic factor Val66Met allele impairs basal and
ketamine-stimulated synaptogenesis in prefrontal cortex. Liu RJ, Lee FS,
Li XY, Bambico F, Duman RS, Aghajanian GK. Biol Psychiatry. 2012 Jun
1;71(11):996-1005. Epub 2011 Oct 29. PMID:22036038
<http://www.ncbi.nlm.nih.gov/pubmed/22036038>
------------------------
The html version of this release contains images of a Scientist monitorring
a patient in scanner at:
<http://www.nimh.nih.gov/images/news-items/zarate_with_monitor.jpg> and
Scanned brain images with response areas highlighted at
<http://www.nimh.nih.gov/images/news-items/ketamine_MEG_scans.png>
###
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