![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 13 of 13. This is the beginning of the thread.
Posted by Cam W. on April 17, 2001, at 16:20:13
dj is having trouble with his modem and asked me to post this article which appeared in today's Globe & Mail
- Cam
When one antidepressant isn't enough
Patients who don't respond to one type of drug
are finding new hope with combination therapies
WALLACE IMMENTuesday, April 17, 2001
Gwen remembers her recurring depression as "the most horrible agony you can experience
and still keep breathing."It was with me every moment and followed me in my dreams," says the Toronto executive,
now in her 40s, with the benefit of hindsight.Her episodes of depression would last more than a year, creating loss, pain and
disruption to her life that forced her to quit two earlier careers because she had no
idea that anything could be done."I finally decided I needed help one day when I was standing on a street corner and began
thinking how easy it would be to jump in front of a speeding truck and end it all," said
Gwen, who asked that her real name not be used.But when she did see a doctor, Gwen proved to be one of the 20 to 30 per cent of people
with severe depression who do not respond to drug treatment, a problem that has
frustrated both patients and doctors for decades.Because Gwen's condition improved only slightly when she took Paxil, one of the most
commonly prescribed antidepressants, her doctor switched her to Wellbutrin, another
antidepressant that has a different action in the brain.Only when her doctor prescribed both drugs together did the depression subside.
"It was like a miracle," said Gwen, who has not experienced depression for more than
three years and now readily copes with the stress of a new career.Indeed, combining drugs is a growing trend in treating patients who, at first, appear
resistant to the soothing effects of antidepressant medications.The new approach has been made possible by the simple fact that there are now so many
drugs with different properties on the market, said Dr. Robert Levitan, head of
depression research at the Centre for Addiction and Mental Health in Toronto.A large number of antidepressants affect serotonin, a substance that regulates activity
within a walnut-sized area of the brain that affects mood, pleasure and appetite. Other
drugs moderate levels of two other brain chemicals, norepinephrine and dopamine.The balance of these three substances is sometimes compared to the harmony of three
tenors singing together. If one of the three is off, the effect can be a jarring
disruption in mood.It appears that in some people, more than one type of treatment is needed to create
harmony, but combining medications still must be done in a clinic that specializes in
treating depression because there are no clear guidelines."We can't tell just by examination what person will respond to which combination. A lot
of it is clinical experience to see what affects the patient," said Dr. Levitan, who is
also associate professor of psychiatry at the University of Toronto."The medication situation is a bit of a mess because drugs for depression were developed
in a haphazard manner," explained Dr. Robert G. Cooke, head of the centre's depression
clinic. The first family of antidepressants -- the tricyclics -- were developed almost
by
accident, when doctors in the 1950s found that patients taking a drug for tuberculosis
also had a brightening of mood. Researchers then had to piece together an explanation of
how the drugs work by studying what parts of the brain they affect.Since then, many drugs known as selective serotonin reuptake inhibitors (SSRIs) -- the
family that started with Prozac -- were developed, but researchers are still not entirely
sure why they work, Dr. Cooke said.Aside from complex brain chemistry, there are several clearly identifiable reasons why
some people don't respond to an antidepressant medication. These are things doctors will
consider before combining medications.For instance, some patients may suffer from some other undiagnosed medical problem which
causes the symptoms of depression. Once the medical condition is identified and
successfully treated the depression often goes away.Doctors will test for low thyroid levels, which can resemble depression, or undiagnosed
cancer, which can cause weight loss and lethargy similar to depression.Another large group of non-responders are people who have abused drugs or alcohol for a
long period of time, Dr. Cooke said.In older people, there is evidence that constriction or hardening of the blood vessels
in
the brain, as well as small strokes or early symptoms of Alzheimer's disease can cause
depression.When a patient doesn't seem to respond to a particular antidepressant, the standard
procedure for doctors is to begin by first trying to increase the dosage of the same drug
to see if that reduces the depression.If that fails, the next step is to substitute another medication in the same family of
drugs that might have a slightly different effect."This is a bit like going from oranges to tangerines. The big unanswered question is,
should we go instead to a very different drug?" said Dr. Patrick McGrath, a
psychopharmacologist at Columbia University in New York.While there are now about 30 brands of antidepressant on the market, most of them have
not been tested in combination because drug companies sponsor most of the research and
focus on the effects of their own products, noted Dr. McGrath.To find out how they might work alone and together, a long-term study, costing
$25-million (U.S) is being organized by the U.S. National Institute of Mental Health. A
total of 2,000 patients who do not respond to a single antidepressant will be divided
into groups and use various other medications or psychotherapy along with antidepressant
use, said Dr. McGrath, who is helping to co-ordinate the study.Results of the study, called Star*D, will not be available for at least three years.
However, the findings from earlier small studies suggest that well over half of the
previously treatment-resistant cases improve if medications are combined or are used
along with other therapies, including psychotherapy.The same study will also look at the augmentation of an antidepressant with something
that can boost the drug's effect. Lithium and thyroid hormone are the most commonly used."A lot of times if depression doesn't respond to one drug the patient wants to give up.
It is important to find something that works early on so the patient keeps at it," Dr.
McGrath said.Even so, the growth of effective options is encouraging more and more patients to seek
treatment, said Dr. Stan Kutcher, head of the department of psychiatry at Dalhousie
University in Halifax.Dr. Kutcher was an adviser to a study by IMS Health that found the number of patients in
Canada who sought treatment for depression went up by as much as 10 per cent in the past
year and a total of 36 per cent over the past five years.This is because awareness of treatments has been raised by media coverage and
drug-company advertising, according to the study by IMS, which advises the pharmaceutical
industry on trends.Still, Dr. Kutcher estimated that as many as three million people in Canada have had at
least one long-lasting episode of depression, but two thirds of them suffer in silence.This is not just having a bad hair day -- to be considered medically depressed you have
to have experienced symptoms for four weeks or more.In most cases, people who seek help have been depressed for more than six continuous
months. In addition, an estimated one per cent of Canadians suffer bipolar shifts between
mania and depression.Many of these depressions are intermittent. An important question that must be given more
research is whether some patients can go off their medication once their depression
lifts, Dr. Cooke said."Our experience with the drugs used since the 1950s is that people don't develop a
tolerance to them. We haven't discovered any terrible ticking time bomb of side effects,"
Dr. Cooke said."If people are taking them and they have effect, it is probably a good idea to continue
to take them."What pills are right for you?
Bromides and opiates: In the early half of the last century, manic-depressed patients
were given opiates or bromides to calm their agitation, but they ended up feeling
sedated.
Mood elevators and stablizers: After the Second World War, mood elevators were available.
They caused intoxicating side effects and were often abused. The natural salt lithium was
found to stabilize mood, but when used alone at doses that relieve depression it can
cause intestinal problems and tremors.
Tricyclics: The 1950s brought the first specific antidepressants, a class of drugs called
tricyclics, including Tofranil and Norpramin. These produce side effects such as dry
mouth or constipation and sometimes extreme drowsiness.
MAOIs: Monoamine oxidase inhibitors were developed to treat both depression and anxiety
and include Manerix and Nardil. They can react with other drugs or foods to affect blood
pressure.
SSRIs: In the late 1980s, a new class of antidepressants earned the nickname "designer
drugs" because they act on specific mood-regulating areas in the brain. Prozac was the
first of many selective serotonin reuptake inhibitors (SSRIs) that elevate levels of
serotonin without affecting other chemical levels in the brain. Other SSRIs include
Celexa, Luvox, Paxil and Zoloft. Prozac has been dogged by the controversy that it may
cause suicide in some people. The drug's maker, Eli Lilly and Co., says there is no good
evidence to support such claims.
SNRIs: Variations on the designer drugs are selective norepinephrine reuptake inhibitors
(SNRIs), such as Effexor, which increases both norepinephrine and serotonin, and
Wellbutrin, which affects brain dopamine but not serotonin. Wellbutrin is marketed on the
basis that it does not reduce sexual desire -- a problem that affects some patients on
SSRIs.
In the works: New drugs being tested in clinical trials include what are known as
substance P blockers, which inhibit release of a hormone in the brain linked to
depression. Other research is looking at corticotropin releasing hormone blockers, which
reduce anxiety and stress in mice.Beyond the medicine cabinet
Aside from antidepressant medications, researchers are exploring other ways to beat the
blues:Herbs: European trials of the herb St. John's Wort have demonstrated some success
alleviating depression, but little is known about effective dosages or side effects. The
U.S. National Institute of Health is now running a long-term test of sustained-release
pills containing the herb.For information, see the Web site http://hypericum.rti.org.
Hormones: Hormone levels also have an effect on the efficacy of antidepressants and
require more study. Women have a higher incidence of depression and research is looking
at the role of estrogen.Small studies have also found thyroid supplements and the natural steroid DHEA
(dehydroepiandosterone) can help improve the response to antidepressants in some
patients.
ECT: For depressions that resist all other treatment, electroconvulsive therapy (ECT)
remains the standard. It has received a lot of bad press in North America in the past,
though long-term studies show that it does not cause damage to the brain. In its modern
form, only a mild shock is used, causing the patient to shiver momentarily. A series of
treatments are sometimes needed before it provides relief. The antidepressant effect of
ECT tends to fade over time and treatment may have to be repeated.But a recent study suggests that the chance of relapse is reduced when ECT is used in
combination with antidepressant and antipsychotic medications.
Implants: Health Canada has just approved a new option of an implantable device that
stimulates the vagus nerve in the neck. Results of a year-long trial by the device's
maker, Cyberonics, Inc., found that about half of patients in a test group reported at
least 50-per-cent improvement in their depression symptoms.About 18 per cent of people who did not respond to drugs responded to them after a year's
use of the implant.
-- Wallace Immen
Posted by SLS on April 17, 2001, at 21:25:46
In reply to Globe and Mail Article From dj on ADs, posted by Cam W. on April 17, 2001, at 16:20:13
> dj is having trouble with his modem and asked me to post this article which appeared in today's Globe & Mail
> - Cam
Although a rare occurence, I have a few comments and corrections. I hope someone will be kind enough to correct my corrections as needed. :-)
> When one antidepressant isn't enough
> Patients who don't respond to one type of drug
> are finding new hope with combination therapies
> WALLACE IMMEN
>
> Tuesday, April 17, 2001
>
>
> Because Gwen's condition improved only slightly when she took Paxil, one of the most commonly prescribed antidepressants, her doctor switched her to Wellbutrin, another antidepressant that has a different action in the brain.
>
> Only when her doctor prescribed both drugs together did the depression subside.
To me, it makes sense to take inventory of drugs that have produced even the mildest of improvements so as to create a list of drugs that might be the best candidates for effective combinations. There might also be clues as to which new drugs to try when taking into consideration which drugs produced improvement as well as those that have produced an exacerbation of depression.
> "We can't tell just by examination what person will respond to which combination.
I am optimistic that one day this will be possible. An examination might comprise of using various brain imaging techniques to determine baseline regional brain activity as well as the brain's reaction to an algorithm of pharmacological challenges.
> "The medication situation is a bit of a mess because drugs for depression were developed in a haphazard manner," explained Dr. Robert G. Cooke, head of the centre's depression clinic.
I disagree with this extreme characterization of haphazard the manner in which these drugs have been developed. The search for effective medications using a "designer" approach based upon chemical structure and binding sites has been around for at least fifteen years. However, without an exact understanding of how the brain works in health and disease, these "ideal" designs often just plain don't work. This is why there still exist paradigms for the screening for antidepressants using animal models.A good example of the purposeful design of a drug is gabapentin (Neurontin). It was developed because of its nearly indentical chemical structure with GABA (gamma aminobutyric acid). However, it failed to bind to the GABA receptor at all. However, fortuitously, gabapentin turned out to act at other sites in such a way as to produce anticonvulsive effects. This was unforseen.
> The first family of antidepressants -- the tricyclics -- were developed almost by accident, when doctors in the 1950s found that patients taking a drug for tuberculosis.
Just for the sake of accuracy, the antituberculosis drug was an MAO-inhibitor known as iproniazid. I believe this serendipitous discovery occured in 1954 and explored more fully by 1957.From: http://www.csusm.edu/DandB/AD.html
"History of Antidepressants
The first two classes of drugs used to treat major depression, the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants were discovered by serendipity. Iproniazid, the first modern antidepressant, was originally developed as an antitubercular drug in the early 1950's. In addition to its ability to treat tuberculosis, iproniazid was observed to elevate mood and stimulate activity in many patients. These effects led researchers to investigate the ability of iproniazid to treat the symptoms of depression. After promising preliminary findings reported in 1957, iproniazid was prescribed widely to patients with major depression. Within the first year it was available as an antidepressant, four hundred thousand depressed people were treated with iproniazid. Subsequent studies demonstrated the ability of this drug to block the activity of monoamine oxidase, the enzyme that destroys the monoamine neurotransmitters (norepinephrine, serotonin and dopamine). Although iproniazid is no longer used as an antidepressant because of toxic side-effects, the effectiveness of this drug led to further interest in the idea that depression might be alleviated by appropriate drugs.
The first tricyclic antidepressant, imipramine, was originally developed in a search for drugs useful in the treatment of schizophrenia. Although clinical trials demonstrated a lack of effect in treating schizophrenia, an astute clinician decided to examine its effectiveness in depressed patients. Early studies in 1957 and 1958 reported that imipramine significantly alleviated symptoms in patients with major depression. Interestingly, although imipramine elevated mood and increased energy in depressed patients, the drug proved to be sedating in individuals without major depression. These effects led to the idea that imipramine was selectively reversing the depression, rather than simply producing a general activating effect. Subsequent biochemical studies on imipramine demonstrated that this drug increased the activity of the monoamine neurotransmitters, norepinephrine and serotonin, by inhibiting their reuptake into neurons."
> About 18 per cent of people who did not respond to drugs responded to them after a year's use of the implant.
The only investigated I know of designed specifically to test VNS for treatment-resistant depression is a pilot study that yielded a 40% response rate. Perhaps the results of a large-scale study have been recently reported. I don't know.
- ScottBiol Psychiatry 2000 Feb 15;47(4):276-86
Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study.
Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, Nahas Z, Haines S, Simpson RK Jr, Goodman R.
Departments of Psychiatry and Neurosurgery, University of Texas Southwestern Medical Center, Dallas 75235-9086, USA.
BACKGROUND: Vagus Nerve Stimulation (VNS) delivered by the NeuroCybernetic Prosthesis (NCP) System was examined for its potential antidepressant effects. METHODS: Adult outpatients (n = 30) with nonpsychotic, treatment-resistant major depressive (n = 21) or bipolar I (n = 4) or II (n = 5; depressed phase) disorders who had failed at least two robust medication trials in the current major depressive episode (MDE) while on stable medication regimens completed a baseline period followed by NCP System implantation. A 2-week, single-blind recovery period (no stimulation) was followed by 10 weeks of VNS. RESULTS: In the current MDE (median length = 4.7 years), patients had not adequately responded to two (n = 9), three (n = 2), four (n = 6), or five or more (n = 13) robust antidepressant medication trials or electroconvulsive therapy (n = 17). Baseline 28-item Hamilton Depression Rating Scale (HDRS(28)) scores averaged 38.0. Response rates ( > or =50% reduction in baseline scores) were 40% for both the HDRS(28) and the Clinical Global Impressions-Improvement index (score of 1 or 2) and 50% for the Montgomery-Asberg Depression Rating Scale. Symptomatic responses (accompanied by substantial functional improvement) have been largely sustained during long-term follow-up to date. CONCLUSIONS: These open trial results suggest that VNS has antidepressant effects in treatment-resistant depressions.
Publication Types:
Clinical trial
Multicenter studyPMID: 10686262 [PubMed - indexed for MEDLINE]
Posted by Cam W. on April 18, 2001, at 0:37:10
In reply to Re: Globe and Mail Article From dj on ADs (long), posted by SLS on April 17, 2001, at 21:25:46
Scott - I've been doing a lot of thinking lately (hard to believe, huh). You know, it seems that no matter what you do for depression (or schizophrenia, for that matter) it's still the same old "1/3 theory". With treatment of without treatment, 1/3 get better, 1/3 stay the same and 1/3 get worse. I really haven't seen any change since the introduction of the SSRIs or other new ADs (the same with the atypical antipsychotics).
Perhaps just actively doing something for the depression causes improvement in some. It has been shown that there are links between placebo effect and relaxation techniques. The link is an increase in the activity of the diffusable neurotransmitter, nitric oxide (NO). Perhaps if we can harness the activity of this molecule we can sustain placebo effect into an actual long term therapeutic effect. This may be off the wall, but I have seen a few studies where there are hints that this may be possible.
Dr.Richelson doesn't believe that the genome is the place to look for correcting depression. I kind of agree with him here. The human genome is just too small to account for the number and variability of personalities in this world. Environmental experiences throughout our life through neuronal plasicity (changes in, and reinforcements of or losses of nerve connections in the brain) (eg efficiancy of synaptic pruning) decides what we will be like. Our particular genome is just the template upon which these changes are effected.
We all agree that it is both our genome and environmental stressors that set the stage for the development of depression (and other mental or physical disorders). It seems obvious to me that the faulty circuitry leading to disorders can be attributed to inadequate neuronal plasticity. There must be a reason for this. Perhaps it is that we have not evolved enough to overcome and accomadate the faster pace of life that began with the Industrial Revolution. Perhaps we have evolved to a genetic deadend because of our complexity and there is no easy way for our bodies to compensate for the increased stresses of the modern world.
Evidence for this can be seen in the dramatic rise in the incidence of depression and bipolar disorder since the second World War. This increase can not totally be shrugged off to better diagnosis or that bipolar disorder is being caused iatrogenically by the use of antidepressant acting as triggers.
I do think that we have to look beyond the reductionist view of neurotransmitter and the receptor site theories of mental illness. Perhaps it would be better to modify secondary receptors (eg G-protein-coupled responses) which effect changes in the production of proteins involved in neuronal plasiticity at the genomic level. In effect, rewiring aberrant signalling involved in disease process.
Whaddaya think Scott. Something different needs to be done because it just seems that all these new improvements turn out to be "same sh**, different day."
A pondering Cam
Posted by jacquie on April 18, 2001, at 6:11:44
In reply to Depression, Antidepressants, Life (ramble) » SLS, posted by Cam W. on April 18, 2001, at 0:37:10
Hi Cam,
Nice to see you post. If I may interject. I am not Scott,
but your pondering is fascinating. I would
like to send it to my shrink. I am so glad there
are people like you who reach beyond the norm. Your
post was very educational.
Jacquie
Posted by SLS on April 18, 2001, at 9:53:09
In reply to Depression, Antidepressants, Life (ramble) » SLS, posted by Cam W. on April 18, 2001, at 0:37:10
Hi Cam.
> Scott - I've been doing a lot of thinking lately
Stop that! :-)
> (hard to believe, huh). You know, it seems that no matter what you do for depression (or schizophrenia, for that matter) it's still the same old "1/3 theory". With treatment of without treatment, 1/3 get better, 1/3 stay the same and 1/3 get worse.
I am surprised by this 1/3 get worse figure. You are in a great position to see how closely this reflects real-life, but it seems way to big to me. I never heard of this. Ouch. That 1/3 hurts. I know that I certainly fit into that category. I have dutifully contributed my share with great fidelity.
Has the rule of 1/3 become the generally accepted tenet among clinicians or researchers, or both? Where do these numbers come from?
I would want to know how much of that 1/3 represents a true exacerbation of depression as opposed to an intolerance to side effects. Not that I know any better, but perhaps this number is most reflective of difficult to treat cases with prior exposure to medications. This 1/3 figure sounds about right for the people posting on Psycho-Babble, where the preponderance fall into that class. What is the ratio of inpatients to outpatients that you service? Relative to the global population of depressives being treated, do you think your population is biased against de novo treatment so that it reflects more difficult to treat cases?
> Perhaps just actively doing something for the depression causes improvement in some.
Yes. This has become a consistent pattern among depressed patients entering NIMH clinical research programs, where they feel that they will finally be cured with the help of the "best of the best". This mild improvement seems to last between one and two weeks.
> It has been shown that there are links between placebo effect and relaxation techniques. The link is an increase in the activity of the diffusable neurotransmitter, nitric oxide (NO).
I didn't know what were the targets or effects of NO. Thanks. I remember sneaking into a physician's lecture in 1992 when the notion of NO being a true transmitter was new and being presented to some for the first time. It seemed like a pretty bazaar finding. I guess I should pay a little more attention to it.
> Perhaps if we can harness the activity of this molecule we can sustain placebo effect into an actual long term therapeutic effect. This may be off the wall, but I have seen a few studies where there are hints that this may be possible.
Hmmm.
> Dr.Richelson doesn't believe that the genome is the place to look for correcting depression.Why not?
> I kind of agree with him here.
I definitely disagree with him here.
> The human genome is just too small to account for the number and variability of personalities in this world.
We are not talking about personalities. We are talking about the physiological dynamics of aberrant brain function, whether triggered by psychosocial stresses or not. I don't think such can be triggered in individuals who are without the biological vulnerabilities necessary to allows for it.
The genome comprises about 40,000 genes that encode for proteins. However, the proteome comprises hundreds of thousands of proteins. This is facilitated by the matrix of gene-transcribed proteins interacting with each other and with other materials present in the physiological environment, including those that are derived from the exogenous environment. The proteome is also responsible for the production of and incorporation of all of the non-proteinacious substances.
There are at least two ways to attack a search for the genes responsible for disease:
1. One can attempt to match genomic loci and identify the alleles responsible for a phenotype by testing for associations between the gene and the disease being studied.
2. One can work backwards. Once the detail of an aberrant physiological mechanism is identified and understood, the suspect protein polymorphisms can be reverse-decoded and its transcription nucleotide sequence derived. This sequence is then matched to its occurrence in the mapped genome. This is quite a bit more efficient to quickly identify pathology.
> Environmental experiences throughout our life through neuronal plasicity (changes in, and reinforcements of or losses of nerve connections in the brain) (eg efficiancy of synaptic pruning) decides what we will be like. Our particular genome is just the template upon which these changes are effected.
We are looking for the source of biological vulnerability, not the myriad conditions that contribute to its expression.
I feel that studying and exploiting genomic information is a valid pursuit in the quest for understanding and treating some mental illnesses. Actually, it is through the elucidation of the genomic details of these mental illnesses that might actually produce a cure, rather than simply developing better ways to control and stabilize their expression. Gene therapy is no longer a fantasy. It is already here.
Studying the genetic has a critical place. Studying the epigenetic has a critical place. We are waiting for both to bear their fruits.
I think you already know my feelings regarding the unequivocal participation of psychosocial stressors and psychogenic evolutions expressed as clinical depression. I hope I am not viewed as having a "unipolar" mentality.
- Scott
Posted by Cam W. on April 18, 2001, at 11:45:48
In reply to Re: Depression, Antidepressants, Life (ramble) » Cam W., posted by SLS on April 18, 2001, at 9:53:09
Scott - Man, I had an eloquent post formulated and them lost the whole damn thing. Here we go again.
I think that the third-third-third "tenet" is more of a clinical rule of thumb rather than hard science ("mooshy" science?). I first heard about with regard to schizophrenia during one of my first days working at Mental Health (strictly outpatient). Many of my colleagues feel that this "tenet" applies to all of their patients, regardless of diagnosis. I do believe that there have been some retrospective studies done on this subject, but one has to be careful with retrospective studies, as they can creatively say whatever you want them to. Off the top of my head, I know of no prospective studies in this area.
In the 1/3 gets worse category you do have to factor in that in most, if not all, cases that depression is a chronic disorder with relapses and remissions of varying lengths. Also, as you say, you must factor in side effects of treatments, as well as placebo effect, patient/doctor concordance (therapeutic relationship), patient expectations and abilities, causation of the disorder, and a myriad of other variables that would be near impossible to factor out.
As for the NO thing, there was a neat study in (oh, God, I didn't copy the reference, just the abstract). Damn! Good day already! I will post the reference in a follow-up. I'm not going to lose this post.
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
The placebo effect and relaxation response: neural
processes and their coupling to constitutive nitric
oxideGeorge B. Stefano a,b A gstefano@li.net, Gregory L. Fricchione a,c,d , Brian T.
Slingsby b and Herbert Benson a
[a]The Mind/Body Medical Institute, CareGroup, Department of Medicine, Beth
Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115,
USA[b]Neuroscience Research Institute, State University of New York at Old
Westbury, Old Westbury, NY 11568, USA[c]The Carter Center Mental Health
Program, 1 Copenhill, 453 Freedom Parkway, Atlanta,GA 30307,
USA[d]Department of Psychiatry, Brigham and Women's Hospital, Harvard
Medical Center, 75 Francis Street, Boston, MA 02115, USA
A Corresponding author. Neuroscience Research Institute, State University of
New York at Old Westbury, Old Westbury, NY 11568, USA. Tel.:
+1-516-876-2732; fax: +1-516-876-2727
Manuscript accepted 17 October 2000;Abstract
The placebo effect appears to be a real phenomenon as is the scientifically demonstrated
and examined relaxation response. Given this, we attempt to understand how these
phenomena work in light of our current understanding of central and peripheral nervous
system mechanisms. Central to our hypothesis is the significance of norepinephrine, nitric
oxide and opioid signaling both in the central and peripheral nervous system. In this
regard, we find that nitric oxide controls norepinephrine processes on many levels,
including synthesis, release and actions. In closing, we conclude that enough scientific
information exists to support these phenomena as actual physical processes that can be
harnessed to provide better patient care.© 2001 Elsevier Science B.V. All rights reserved.
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~As for the genome thing. I really have to disagree with you on the genome project doing much more than finding genetic links to diseases. The more I look into this, the greater the role environmental factors play in our development and make-up. Everything we say, do or will do depends on what we have done in the past. You could expand this fatalistic view to environmental factors changing genes or gene expression in your parents, your parent's parents, ad nauseum. I know this philosophic view doesn't hold any scientific water, but it is interesting to ponder.
So, what I am saying is that it is not the genome that is determining how you end up. It is the secondary messengers, acting from receptor stimulation, using the genome as a template to put proteins and enzymes where the second messengers say they need to be placed. Yes, introns and exons of genes play a big role in deciding this, but ultimately it is how the cascade of secondary messengers line-up which determine how the template is to be used. If we modify the cascade, we modify the protein, and these modifications will be different for everyone (although there may be some homogeneity across disorders). The protein or enzyme which is malfunctioning may not necessarily be an aberrant genetic mutation, it may be being placed wrong once it leaves the nucleus.
We may be able to eventually tell which proteins and enzymes regulate neuronal plasticity and be able to better target abnormalities causing (let's say) depressive symptoms, but I doubt we will be able to do this by changing the genome. Many different processes will use that enzyme or protein in different functions. If we target the enzyme or protein in the DNA we may be doing more damage other places. Like sickle cell anemia being preventative for malaria, depression may be preventative for something else (eg perhaps having some protective role in slowing the incidence of full blown psychoses - this is just a fictitious example). It may be better to locally target secondary messenger systems and leave the DNA alone.
I believe that biologic vulnerability is only one of several avenues that need to be explored. Yes, it is interesting to be able to predict who is vulnerable, but it would be better to be able to fix the end point problem (with minimal disruption to other systems and avoid stigmatization in biologically vulnerable people who will never show the disorder). I guess you could say that I like epigenetic solutions rather than genetic ones.
Just my views - Cam
Posted by Cam W. on April 18, 2001, at 11:57:01
In reply to Re: Depression, Antidepressants, Life (ramble) » SLS, posted by Cam W. on April 18, 2001, at 11:45:48
The placebo effect and relaxation response: neural processes and their coupling to constitutive nitric oxide George B. Stefano, Gregory L. Fricchione, Brian T. Slingsby & Herbert Benson Brain Research Reviews, 2001, 35:1:1-19
> ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
The placebo effect and relaxation response: neural processes and their coupling to constitutive nitric
oxide George B. Stefano a,b A gstefano@li.net, Gregory L. Fricchione a,c,d , Brian T.Slingsby b and Herbert Benson a
[a]The Mind/Body Medical Institute, CareGroup, Department of Medicine, Bet Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115,USA
[b]Neuroscience Research Institute, State University of New York at Old Westbury, Old Westbury, NY 11568, USA
[c]The Carter Center Mental Health Program, 1 Copenhill, 453 Freedom Parkway, Atlanta,GA 30307, USA
[d]Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical Center, 75 Francis Street, Boston, MA 02115, USA.
A Corresponding author. Neuroscience Research Institute, State University of New York at Old Westbury, Old Westbury, NY 11568, USA. Tel.:
+1-516-876-2732; fax: +1-516-876-2727
Manuscript accepted 17 October 2000;Abstract
The placebo effect appears to be a real phenomenon as is the scientifically demonstrated and examined relaxation response. Given this, we attempt to understand how these phenomena work in light of our current understanding of central and peripheral nervous system mechanisms. Central to our hypothesis is the significance of norepinephrine, nitric oxide and opioid signaling both in the central and peripheral nervous system. In this
regard, we find that nitric oxide controls norepinephrine processes on many levels, including synthesis, release and actions. In closing, we conclude that enough scientific information exists to support these phenomena as actual physical processes that can be harnessed to provide better patient care.
© 2001 Elsevier Science B.V. All rights reserved.
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Posted by SLS on April 18, 2001, at 20:56:20
In reply to Re: Depression, Antidepressants, Life (ramble) » SLS, posted by Cam W. on April 18, 2001, at 11:45:48
Cam.
To continue the dialectic...
> As for the genome thing. I really have to disagree with you on the genome project doing much more than finding genetic links to diseases.
No. It is attempting to discover how the body manages its own functions by reading and understanding the blueprints. Finding genetic links to phenotypes, including diseases, is just one of the steps involved in this process.
> So, what I am saying is that it is not the genome that is determining how you end up.
Neither is it the environment.
The genome surely defines boundaries and potential. It influences the direction of growth in any particular environment.
Both contribute.
I am not focused more on one than the other. I just wanted to express my feelings that the pursuit of the human genome is not without great importance and application. Much will come of it. That is probably an understatement. I think it is counterproductive to describe what it is not without appreciating what it will be. I don't think we can fully understand the potential of deciphering the genome until we do. Its utility will depend upon the cleverness of man to exploit this information. Unfortunately, cleverness is not exclusive to those with good intentions.
> It is the secondary messengers, acting from receptor stimulation, using the genome as a template to put proteins and enzymes where the second messengers say they need to be placed. Yes, introns and exons of genes play a big role in deciding this, but ultimately it is how the cascade of secondary messengers line-up which determine how the template is to be used. If we modify the cascade, we modify the protein, and these modifications will be different for everyone (although there may be some homogeneity across disorders). The protein or enzyme which is malfunctioning may not necessarily be an aberrant genetic mutation, it may be being placed wrong once it leaves the nucleus.
Change the expression of the genes responsible for placement. :-)
> We may be able to eventually tell which proteins and enzymes regulate neuronal plasticity and be able to better target abnormalities causing (let's say) depressive symptoms, but I doubt we will be able to do this by changing the genome.
It is not the genome that is necessarily targeted for change. Decoding the genes and understanding how they function could be used to regulate the expression of those genes within the neuron that serve to regulate membrane and cytoplasmic structure and activity. One example might be to change the sensitivity of receptors. Perhaps this could be accomplished best by bypassing the dysregulated cascade of second messenger events (the communication mechanisms by which the neuron regulates its own gene activity) and establish a new equilibrium by manipulating the genes directly; an equilibrium that might maintain itself once gene manipulation treatment is discontinued.
> It may be better to locally target secondary messenger systems and leave the DNA alone.
Yeah. That sounds better to me too.
> Many different processes will use that enzyme or protein in different functions. If we target the enzyme or protein in the DNA we may be doing more damage other places.
I guess this is sort of like what happens with MAO inhibitors.
However, the relevant genes might be specific for expression in neurons. This is an integral part of cell differentiation. This would take care of your concern. Another perspective might be that if a particular gene and the enzyme it codes for are defective, correcting this one enzyme globally might not do very much throughout the body except to act as it should nominally in a state of good health. I am interested to know if the immune system would react to the "corrected" proteins as antigen.
> I believe that biologic vulnerability is only one of several avenues that need to be explored.
Of course. That's exactly what the human genome project is designed to help accomplish.
> Yes, it is interesting to be able to predict who is vulnerable, but it would be better to be able to fix the end point problem...
As opposed to fixing the starting point?
> ...(with minimal disruption to other systems
This might be an argument in favor of fixing the starting point rather than juggling multiple events pharmacologically at the endpoint and hoping you don't affect adversely the activity of other cells elsewhere in the body. Perhaps we will be capable of localizing gene therapy. Using the strategic placement of genetically-corrected stem-cells might do the job.
> ...and avoid stigmatization in biologically vulnerable people who will never show the disorder).
This will probably be the most potent issue regarding such genetic identification. It is not limited to mental illness.
> I guess you could say that I like epigenetic solutions rather than genetic ones.
Regulating the expression of existing genes is epigenetic, regardless of whether it is accomplished through the manipulation of cytoplasmic or nuclear events. Of course, not all somatic interventions involve gene regulation.
Now, for the record...
I was careful enough to use the phrase "some mental illnesses" when referring to genetic determinants. I purposely did not include the word "depression". I was also careful to include the phrase "psychogenic evolution" as a mode by which a "clinical" (not biological) depression is produced. I am a big believer in the role, and possibly the sole role, that epigenetic influences can produce things like depression and PTSD. I like the way you present neural plasticity and developmental neurological events like pruning. Regarding prominent genetic contributions and the utility of exploiting their identification, I really had in mind bipolar disorder and schizophrenia. However, I don't doubt that many unipolar depressions have a genetic etiology as hard as that of bipolar disorder.
Disclaimer: I am just running off at the mouth. I can't find anything to watch on T.V. 57 channels and nothin' on.
- Scott
Posted by Cam W. on April 19, 2001, at 9:17:56
In reply to Re: Depression, Antidepressants, Life (ramble) » Cam W., posted by SLS on April 18, 2001, at 20:56:20
Scott - It's now a wait and see issue and let science catch up with us. It's been a while since we've done that. Let's not wait so long next time. Thanks for the great discussion. - Cam
Posted by SLS on April 20, 2001, at 16:57:39
In reply to Re: Globe and Mail Article From dj on ADs (long), posted by SLS on April 17, 2001, at 21:25:46
I think I mistook the meaning of the following passage:
> > About 18 per cent of people who did not respond to drugs responded to them after a year's use of the implant.
I had replied:
> The only investigated I know of designed specifically to test VNS for treatment-resistant depression is a pilot study that yielded a 40% response rate. Perhaps the results of a large-scale study have been recently reported. I don't know.
When I reread the passage more closely, I realized that the reference to an 18% response rate was not a description of the antidepressant efficacy of VNS. Rather, it seems that 18% of those patients who used the VNS device for a year or more became responsive to those medications that had previously been ineffective. I think ECT might produce a similar effect, but I would have to look into it more closely.
- Scott
Posted by Cam W. on April 20, 2001, at 19:31:54
In reply to Re: Globe and Mail Article From dj - My Mistake, posted by SLS on April 20, 2001, at 16:57:39
Archives of General Psychiatry / volume:58 (page: 199)
Deliberate Seizure Induction With Repetitive Transcranial Magnetic Stimulation in Nonhuman Primates Sarah H. Lisanby, MD; Bruce Luber, PhD; Harold A. Sackeim, PhD; A. D. Finck, MD; Charles Schroeder, PhD February 2001.Scott - The above researchers, in a letter to the editor of the Archives of General Psychiatry in February, 2001, found that when you turn up the magnetism on the TMS you can induce seizures that have antidepressant effects similar to ECT in adolescent 'Macaca mulata'. rTMS has an advantage ove ECT in that the focal point of stimulation can be localized and more controlled because the electrical currents of ECT are blocked and spread out by the skull, whereas magnetic fields pass through virtually unimpeded. This could eventually mean that there would be fewer cognitive side effects with the same (or better) antidepressant effects with rTMS. They are now working to fine tune the rTMS to find proper levels of magnestism and better ways to reduce coil heating.
Just thought that this was kinda cool. - Cam
Posted by SLS on April 21, 2001, at 10:20:31
In reply to Re: Seizure Induction with rTMS » SLS, posted by Cam W. on April 20, 2001, at 19:31:54
> Archives of General Psychiatry / volume:58 (page: 199)
> Deliberate Seizure Induction With Repetitive Transcranial Magnetic Stimulation in Nonhuman Primates Sarah H. Lisanby, MD; Bruce Luber, PhD; Harold A. Sackeim, PhD; A. D. Finck, MD; Charles Schroeder, PhD February 2001.
>
> Scott - The above researchers, in a letter to the editor of the Archives of General Psychiatry in February, 2001, found that when you turn up the magnetism on the TMS you can induce seizures that have antidepressant effects similar to ECT in adolescent 'Macaca mulata'. rTMS has an advantage ove ECT in that the focal point of stimulation can be localized and more controlled because the electrical currents of ECT are blocked and spread out by the skull, whereas magnetic fields pass through virtually unimpeded. This could eventually mean that there would be fewer cognitive side effects with the same (or better) antidepressant effects with rTMS. They are now working to fine tune the rTMS to find proper levels of magnestism and better ways to reduce coil heating.
>
> Just thought that this was kinda cool. - CamWow. I wouldn't have guessed it capable of that. I would like to know more about that.
The NIMH has just begun a study using a higher *frequency* rTMS than they had previously. They have set out to compare 1 stimulation per second to 20 stimulations per second. They are focusing on treatment-resistant unipolar and bipolar depression They are still looking for volunteers.
1-800-518-7326
or
1-301-496-6827
- Scott
By the way, I ran across an abstract that indicated that ECT reduces the secretion of CRH.
Posted by SLS on April 21, 2001, at 11:46:38
In reply to Re: Seizure Induction with rTMS » SLS, posted by Cam W. on April 20, 2001, at 19:31:54
Dear Cam,
The more I think about this, the more excited I become. I am going to put this on my list of alternatives. I can't wait to see what comes of it.
Thanks again.
- Scott
> Archives of General Psychiatry / volume:58 (page: 199)
> Deliberate Seizure Induction With Repetitive Transcranial Magnetic Stimulation in Nonhuman Primates Sarah H. Lisanby, MD; Bruce Luber, PhD; Harold A. Sackeim, PhD; A. D. Finck, MD; Charles Schroeder, PhD February 2001.
>
> Scott - The above researchers, in a letter to the editor of the Archives of General Psychiatry in February, 2001, found that when you turn up the magnetism on the TMS you can induce seizures that have antidepressant effects similar to ECT in adolescent 'Macaca mulata'. rTMS has an advantage ove ECT in that the focal point of stimulation can be localized and more controlled because the electrical currents of ECT are blocked and spread out by the skull, whereas magnetic fields pass through virtually unimpeded. This could eventually mean that there would be fewer cognitive side effects with the same (or better) antidepressant effects with rTMS. They are now working to fine tune the rTMS to find proper levels of magnestism and better ways to reduce coil heating.
>
> Just thought that this was kinda cool. - Cam
This is the end of the thread.
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