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Electromagnetic Treatments for Non-responsive Depression Seek to Improve on ECT 7-4-08
There's a new wave of research into targeted electromagnetic treatments for
resistant depression, all aiming to relegate traditional electroconvulsive
therapy (ECT) to obsolescence.
An estimated 15% to 20% of depressed patients don't respond to drug or talk
therapies, sending many into the realm of ECT. Although 60% to 70% of patients
respond to ECT, its baggage includes frequent adverse side effects and a bad PR
problem.
Now, a variety of alternative approaches that apply electrical currents to the
brain are in the research pipeline, and one is FDA approved. They include:
* Vagus nerve stimulation
* Magnetic seizure therapy
* Repetitive transcranial magnetic stimulation
* Deep brain stimulation
* Transcranial direct current stimulation
* Implantable cortical stimulation
Vagus nerve stimulation
Vagus nerve stimulation is the only electromagnetic stimulation therapy besides
ECT that has been approved by the FDA, although it too has been dogged by
controversy.
The approval is specifically for unipolar or bipolar depression lasting at least
two years, during which patients have failed at least four other adequate
treatments, and who have had multiple previous depressive episodes.
Vagus nerve stimulation involves implantation of a pacemaker-like device in the
patient's chest, with wire leads wrapped around the vagus nerve in the neck.
The idea came from its earlier, successful use in treating epilepsy. Clinicians
noticed mood improvements following the device's activation, leading its
commercial developer, Cyberonics Inc., to sponsor formal clinical studies.
According to A. John Rush, M.D., of the University of Texas Southwestern Medical
Center in Dallas, who led the device's pivotal trial in depression, pulses
delivered to the vagus nerve "go to specific areas in the central nervous system
that control mood, motivation, sleep, appetite, and other symptoms that are
relevant to depression."
But the procedure's safety-benefit balance has been questioned. The FDA approved
the device in 2005 despite staff objections that the efficacy data were weak. In
the pivotal study, only 30% of patients (versus 10% of sham-treated patients)
showed measurable responses after one year on the clinician-administered
Hamilton Depression Rating Scale, and even fewer -- 22%, compared with 12% of
sham-treated patients -- reported significant improvement on a self-assessment
index.
Those objections were reinforced by the Centers for Medicare and Medicaid
Services in a May 2007 decision to deny Medicare coverage for the device, saying
it was "not reasonable and necessary" for treating resistant depression.
The CMS decision has effectively curtailed use of the device. Cyberonics
recently reported that depression-related sales have fallen by more than 80%
since the CMS ruling, even as sales for use in epilepsy rose by 10%.
Low response rates are not the only downside to vagus nerve stimulation. Once
the electrodes are attached to the vagus nerve, they cannot be removed without
risk to the nerve. The FDA therefore mandated that the device's labeling include
a black-box notice that implantation is irreversible.
It is also invasive, unlike ECT and most other neurostimulation approaches.
On the other hand, Dr. Kennedy noted, it has an established safety record thanks
to its 10 years of use in epilepsy. The main adverse effect is vocal hoarseness.
Transcranial magnetic stimulation
Transcranial magnetic stimulation is next in the pipeline, with the FDA now
considering a marketing application from Neuronetics. The firm expects a
decision within a few months.
Its system looks like a dentist's chair, except that the moveable arm carries a
fist-sized magnetic coil instead of a drill.
Like ECT, it is essentially an electrical therapy, except that it induces
currents within the brain magnetically, rather than by delivering current
directly through wires.
It has been used extensively as a research tool, because placing the coil over
certain regions of the brain can cause involuntary movements or affect sensory
processes. It can thus be used to map brain function, for example.
Since the first clinical studies in depression appeared in the early 1990s,
transcranial magnetic stimulation has evolved to deliver energy in pulses, and
with a series of treatments given over weeks or months. For this reason, it is
often called repetitive transcranial magnetic stimulation.
For example, a recent study with the Neuronetics system involved five sessions
per week for four to six weeks.
The main target brain region has been the dorsolateral prefrontal cortex. That's
because this region is known to be involved with mood, and also because it sits
near the top surface of the brain. Because the strength of magnetic fields falls
off exponentially with distance from the coil, deeper structures such as the
cingulate and limbic cortexes are beyond reach.
Head-to-head clinical studies with transcranial magnetic stimulation and ECT
have found similar response rates in patients with non-psychotic depression.
Cognitive side effects have generally been less common with the magnetic
therapy, according to Dr. Kennedy. The most common adverse effects have been
transient scalp discomfort and pain and tinnitus. A few cases have been reported
in which the treatment appeared to induce seizures or manic episodes.
A pivotal study sponsored by Neuronetics, reported late last year, assigned 164
patients to four weeks of treatment with the magnetic therapy or a sham version.
The active therapy led to significantly greater mean reductions in depression
symptom scores.
But fewer than a quarter of patients had more than 50% reduction in symptoms
scores.
On the other hand, the magnetic therapy performed somewhat better in another
sham-controlled trial conducted at the University of Iowa and reported at the
American Psychiatric Association meeting in May. In 94 patients with vascular
depression, nearly 40% showed major symptom relief and 28% had complete
remission.
Dr. Kennedy noted that little is known about the durability of response to
transcranial magnetic stimulation. In an open-label extension to the Neuronetics
pivotal study, in which patients were maintained on anti-depressant drugs, more
than 35% required additional magnetic therapy sessions within six months to deal
with recurrent symptoms.
Magnetic seizure therapy
Magnetic seizure therapy is a more intense version of transcranial magnetic
stimulation. It harkens back to the original goal of ECT, using a magnetically
induced current to provoke a clonic seizure.
It is intended to be more focused in the cortex than ECT, with the aim of
reducing the cognitive side effects.
A series of preclinical studies and case reports published from 2000 to 2006
supported the idea, but the only one involving more than one patient found that
it was also less effective than ECT.
Led by Sarah Lisanby, M.D., of Columbia University here, a colleague of ECT
researcher Harold Sackeim, M.D., the case-matched study of 20 patients found
that both treatments produced significant reductions in depression scores, but
residual symptoms were more pronounced in those receiving the magnetic therapy
(mean Hamilton score 6 for ECT versus 14 for magnetic seizure therapy, P<0.05).
The results were published in 2006 in Anesthesia and Analgesia.
There have been no published reports on the treatment since then, but
ClinicalTrials.gov lists a 75-patient randomized, ECT-controlled trial led by
Dr. Lisanby as currently recruiting patients, with a 2010 completion date. Dr.
Lisanby could not be reached for comment.
Transcranial direct current stimulation
First studied for depression in the 1960s -- and in other psychiatric disorders
as far back as the early 19th century -- transcranial direct current stimulation
is an ECT-Lite.
It delivers current to the brain via electrodes placed on the scalp, as does ECT.
But it involves much lower currents -- no more than 2 mA, compared with 400 to
900 mA in ECT -- so that it does not induce seizures or require anesthesia.
As currently studied, it is delivered in short daily sessions over a period of
weeks, similar to transcranial magnetic stimulation.
As with other electromagnetic therapies, the mechanism of action in depression
remains unclear. It appears to modulate neuronal excitability, but beyond that
little is known.
It's so simple that an Internet site describes how individuals can create their
own treatment system with a nine-volt battery, two wires, and damp sponges.
However, much of the recent research on the treatment has been conducted with
commercial stimulators produced by Magstim Co. in Wales.
One of the leading investigators has been Felipe Fregni, M.D., of Beth Israel
Deaconess Medical Center in Boston.
Last year, his group published a randomized, sham-controlled study -- the first
ever for this approach -- involving 40 patients with recently untreated major
depression. There was no requirement to have failed earlier therapies.
The trial compared treatment applied to the left dorsolateral prefrontal cortex
with stimulation of the occipital cortex -- which Dr. Fregni and colleagues
anticipated would have no effect, serving as an "active control" -- and with
sham treatment.
The left dorsolateral treatment was modestly effective, according to the
researchers' report in the International Journal of Neuropsychopharmacology.
They found a mean reduction of 40.4% in depression scores, versus a 21.3%
reduction with the occipital cortex treatment and 10.4% with sham therapy.
About 38% of patients receiving the left dorsolateral treatment had at least 50%
reductions in symptom scores, compared with 20% of sham-treated patients and 0%
of those receiving the occipital cortex stimulation.
However, whether patients with more treatment-resistant depression could expect
such response rates is unknown.
"It's difficult to predict right now," Dr. Fregni said.
Adverse effects have included headaches and itching and redness where the
electrodes are placed.
Implantable cortical stimulation
Another early-stage investigational technology takes vagus nerve stimulation a
step farther. Instead of delivering electrical pulses to a nerve, it sends them
to the surface of the brain.
Seattle-based Northstar Neurosciences is testing a system that, like vagus nerve
stimulation, inserts a pulse generator in the patient's chest. An electrical
lead is passed into the skull through a surgically drilled hole, terminating on
the dural membrane over the cortex.
In a recent sham-controlled study of 11 treatment-resistant patients sponsored
by Northstar, the therapy produced mean improvements of about 22% in depression
symptom scores after eight weeks.
After one year, the mean degree of improvement increased to 32%, according to
the company's chief medical officer, Brian Kopell, M.D.
However, prospects that the device would reach the market dimmed earlier this
year when it failed to show a significant benefit in another clinical trial
involving stroke survivors. That had been the product's lead indication. The
failure cast doubt on Northstar's ability to complete pivotal trials in
depression and tinnitus, another application the firm has pursued.
Deep brain stimulation
Currently among the least advanced of the various electromagnetic stimulation
approaches to depression, deep brain stimulation is nevertheless considered one
of the most promising.
That is mainly because it already has a long track record, thanks to its use in
thousands of people with Parkinson's disease. Its safety and the technical
aspects of placement are therefore considered to be relatively well understood.
The technology is similar to vagus nerve and implantable cortical stimulation,
except that the electrical leads are extended into a particular brain region
called BA25, located within the cingulate cortex. Thus, it requires drilling a
hole in the skull, as well as an incision in the chest for placing the
pacemaker-like electrical pulse generator.
Only a few uncontrolled case series have been reported thus far for deep brain
stimulation in depression, but these have been extremely positive.
In a 16-patient trial at the Cleveland Clinic, reported in April at the American
Association of Neurological Surgeons meeting, half showed at least 50% reduction
in depression symptoms for one year. (See: AANS: Brain Pacemaker Effective in
Resistant Depression)
At another recent meeting, Dr. Kennedy presented findings from a multicenter
study (also uncontrolled) in which nine of 16 patients had at least 40%
reductions in symptom scores.
However, he conceded that moving to large randomized studies would be difficult
because of the invasiveness issue. Deep brain stimulation requires a
neurosurgeon to implant the leads.
Both studies involved patients with long-established, severe depression that had
resisted multiple anti-depressant drugs and ECT.
Electroconvulsive therapy
ECT was first developed in the 1930s, out of an even older medical tradition
holding that seizures could alleviate a number of psychiatric conditions. ECT
was initially tried in schizophrenia, but except for some acute psychotic
states, it was not effective. But psychiatrists soon found that it was effective
against severe depression.
As practiced through the 1940s, it was a frightening and dangerous procedure.
Later, researchers found that side effects could be reduced without sacrificing
efficacy when it was modified to deliver short electrical pulses, rather than
the long blasts of current first used, along with general anesthesia and
neuromuscular blockers.
Nevertheless, patients still generally emerge from an ECT session feeling
confused and disoriented, lasting about an hour. Short-term memory is also
frequently disrupted. Occasional reports of longer-term memory loss still come
forth, contributing to persistent controversy about the procedure and psychiatry
in general.
It probably doesn't help that ECT's mechanism of action remains unclear. Effects
on neurotransmitter, cytokine, and neurotrophic factor pathways have been
suggested, but no single mechanism has been definitively identified, according
to Sidney Kennedy, M.D., a prominent neurostimulation researcher at the
University of Western Ontario in London, Ontario.
But progress against side effects continues. A study published last month by
Harold Sackeim, M.D., of Columbia University here, and colleagues in Brain
Stimulation found that shortening the pulses to 0.3 milliseconds, versus the
standard 1.5 milliseconds, reduced memory deficits significantly in a randomized
trial.
In ongoing studies, Dr. Sackeim and colleagues are also exploring alternative
electrode placements so that seizures are induced only in the frontal lobes, an
approach known as focal electrically-applied seizure therapy.
Looking to the future
"We remain early in the development of alternative brain stimulation
techniques," wrote Paul Fitzgerald, M.B.B.S., Ph.D., of Monash University in
Victoria, Australia, and Zafiris Daskalakis, M.D., of the Centre for Addiction
and Mental Health in Toronto, recently in Current Opinion in Psychiatry.
They noted that clinical data even for vagus nerve stimulation, which is
FDA-approved, are "shallow" and dominated by company-sponsored research.
"The development of large multi-site trials of techniques such as repetitive
transcranial magnetic stimulation and vagus nerve stimulation, including those
independently funded, is warranted," they said.
Dr. Kennedy said that no matter how effective the approaches involving surgery
prove to be, they would never become widely used.
Rather, they will probably always be reserved for those patients who fail
everything else, including ECT.
"I don't see psychiatry as going to an invasive procedure early," he said.
By the same token, the non-invasive technologies may find niches earlier in the
treatment cycle.
Dr. Fregni pointed out that ECT is already known to be effective in the
treatment-resistant population.
Although not every patient responds to ECT, another unmet clinical need is for
simple and benign alternatives to anti-depressant drugs that can be tried before
resorting to ECT, he suggested.
The transcranial stimulation technologies, both electrical and magnetic, "are
offering something less invasive," he said.
The non-invasive approaches also offer other opportunities, Dr. Fregni said.
One possibility he plans to study is to combine transcranial direct current
stimulation with cognitive therapy -- that is, in the same room at the same
time.
He said the electrical stimulation may "prime the brain" to be more receptive to
the thought remodelling that cognitive therapy is intended to accomplish.
"You might be able to enhance the efficacy of cognitive therapy," he said.
At the moment, only the direct current therapy is feasible for this approach,
according to Dr. Fregni. Present-day magnetic stimulation devices are too noisy
and distracting, he said.
Drs. Fitzgerald and Daskalakis said a "neglected" niche that non-invasive
neurostimulation therapies might fill is in maintenance treatments. ECT, for
example, is notorious for the speed with which depression symptoms return after
stopping treatment.
"It is timely to consider the development of decent studies" in this area, they
suggested.
For all the electromagnetic stimulation therapies, Dr. Fregni said, considerable
research still needs to be done to optimize the stimulation parameters.
In each case, the strength of the electric current or magnetic field, the
duration of pulses, and the spatial location can be varied. Finding the best
combinations is a time-consuming job.
Indeed, as Dr. Sackeim's continued tinkering with ECT suggests, 70 years may not
be enough to complete it.
Comment:
Everyone gets depressed. Some people cant get out of it! The sad fact is medical science has made a fortune off of human suffering that they have never intended to fix. If some one is severely depressed all of the time there is often a physical reason why. Allopathic Physicians were never trained to look at a patient that way. Instead of doing necessary blood work they just give you a script and why not? If they don't and you commit suicide they can be sued. This is just the situation we have created.
If you or a love one are severely depressed, have all normal blood counts checked (CBC), all hormone levels: thyroid, parathyroid, estrogen, progesterone, pregnenolone, testosterone, DHEA, melatonin, cortisol, and anything else you might need. Test for allergies both food and environmental especially molds. Eat a gluten free diet. Get tested for candida and aspergilliosis.