![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 24 of 24. This is the beginning of the thread.
Posted by JohnL on October 28, 2000, at 8:59:45
Hi all,
In other threads there has been debate off and on about how long it takes antidepressants to work. I've seen antidepressant medication labels that say "though you may feel benefits in as little as 4 days, it may take up to 2 weeks for the effect". Anyone who knows me knows that I endorse Dr Jensen's views which are founded on quick responses. It's a lot more complicated than that, but that is the foundation. So I wondered, what is in peer-reviewed literature concerning this topic? I went to the research section of www.mentalhealth.com, typed in "early AND onset AND antidepressant", and clicked on GO. Below is just a sampling of what's out there in the clinical world.I have shortened them with "..." for easier reading. But to read the whole thing, they're easy to find at mentalhealth.com. There are plenty of others as well.
The last one in particular is the whole reason Jensen looked at quick responses not as a fluke, but as a real phenomenon that should be explored and utilized in practice. Especially if speed to recovery is at all important in someone's treatment. I don't mean this to be another pitch for Jensen, but rather evidence that quick responses (3 days to 2 weeks) do indeed exist in the peer-reviewed conventional psychiatric world we all subscribe to.
Also notice how different drugs all provided quick responses in a sizable portion of the population. I believe it was pure luck. That is, those patients who experienced quick response just happened by luck to choose a medication that 1)targeted their problem, 2)was a good molecular fit for their system. If we research this topic deeper, we find that these quick responses exist across the whole spectrum of psychiatric medications. A portion of every sample are going to get 'lucky'. An organized method to increase the odds of finding that lucky medicine is needed. Despite considerable skepticism at this board, that's what Jensen attempts to do. Read on.
1: Depress Anxiety 1999;9(2):54-60
Related Articles, Books, LinkOut
Double-blind comparison of citalopram and placebo in
depressed outpatients with melancholia.
Mendels J, Kiev A, Fabre LF
Therapeutic Services Inc., Philadelphia, Pennsylvania, USA
….On the HAM-D, citalopram patients exhibited significantly greater
improvement than placebo patients AFTER 1 WEEK of double-blind treatment
and at all subsequent study visits….
….results of this study indicate that citalopram is safe and effective in the
treatment of depressed patients with melancholia, and is associated with a
favorable side effect profile and a potentially rapid onset of action.
1: J Psychiatry Neurosci 2000 Sep;25(4):337-46
Preliminary randomized double-blind
placebo-controlled trial of tryptophan combined with
fluoxetine to treat major depressive disorder:
antidepressant and hypnotic effects.
Levitan RD, Shen JH, Jindal R, Driver HS, Kennedy SH, Shapiro
CM
Clarke Division, Centre for Addiction and Mental Health, Toronto, Ont.
robert_levitan@camh.net
….[RESULTS: During the first week of treatment,
there was a significantly greater decrease in HDRS-29 depression scores,
and a similar trend in BDI scores, in the tryptophan/fluoxetine group than
in the placebo/fluoxetine group. No cases of serotonin syndrome occurred,
and the combination was well tolerated, although the 4 g per day dosage
of tryptophan produced daytime drowsiness. CONCLUSIONS:
Combining 20 mg of fluoxetine with 2 g of tryptophan daily at the outset
of treatment for major depressive disorder appears to be a safe protocol
that may have both a rapid antidepressant effect and a protective effect
on slow-wave sleep….1: Brain Inj 1999 Aug;13(8):637-42
Moclobemide in the treatment of major depressive
disorder (DSM-3) following traumatic brain injury.
Newburn G, Edwards R, Thomas H, Collier J, Fox K, Collins C
Rotorua Rehabilitation Clinic, New Zealand.
…..Mean HAM-D reduction
was 81% and HAM-A reduction 81%. Of the 26 subjects 23 were
defined as responders. Onset of action was rapid, with 17 responding by
day 3.…
1: Encephale 1999 Jun;25 Spec No 2:49-54
Related Articles, Books, LinkOut
[Therapeutic action lag time and resistance to
treatment].
Peretti CS
Service de Psychiatrie Adultes, CHU de Reims.
….The literature recommends at least two determinations per
week over the first two weeks of treatment….
….Venlafaxine seems to accelerate the response (day 4) and be superior to
a comparator (Clerc et al., 1996; Guelfi et al., 1995). The study conducted
by Guelfi, in France, in patients presenting with severe depression was
designed to evidence the efficacy of venlafaxine in melancholia. In 1996,
Benkert published a double-blind study comparing venlafaxine and
imipramine in severe depressions. Both studies stressed the rapid action
onset of venlafaxine (between day 4 and week 2) in severe depressions.1: J Affect Disord 1999 Jun;53(3):275-8
Clonazepam in the treatment of prolonged depression.
Morishita S, Aoki S
Department of Psychiatry, Kawasaki Medical School, Kurashiki, Japan.
BACKGROUND: The purpose of this paper was to examine the optimal
adjunctive dose of clonazepam for the treatment of prolonged depression.
METHODS: Sixty nine patients with prolonged depression were enrolled
in an open trial over a 4 week period during which clonazepam was added
to their medication. RESULTS: A daily dose of 3.0 mg clonazepam as
augmentation was significantly more effective than doses of 1.5 mg and
below. Most of the improved patients showed a rapid onset of action
within 2 weeks, and side effects were not severe.
1: Int Clin Psychopharmacol 1997 Jul;12 Suppl3:S21-8
Early onset of therapeutic action in depression and
greater efficacy of antidepressant treatments: are they
related?
Blier P, Bergeron R
Nurobiological Psychiatry Unit, McGill University, Montreal, Canada.
Until recently, several weeks of treatment were required to obtain a
clinically significant antidepressant response using pharmacotherapy. Now
treatment strategies have been developed that appear to produce an early
onset of action in major depression.. …
…..We conclude
that a treatment strategy producing a rapid onset often, but not invariably,
has greater efficacy than a treatment producing a slower onset. These
preclinical and clinical observations may help to devise rapid treatments
for major depression that will be effective in a greater proportion of
patients than at present.
John
Posted by Cam W. on October 28, 2000, at 10:53:08
In reply to 3Day to 2 Week Responses. Proof, not myth., posted by JohnL on October 28, 2000, at 8:59:45
John - Sorry to step into this, but if you can check the original articles (not MEDLINE abstracts) you will find that greater than 80% (possibly higher) of the studies that claim quick response (less than 2 or 3 weeks) are funded by the company who make the drug.
I usually attribute early response of antidepressants to positive expectation (including, but not exclusively placebo response) or misattribution of the start-up side effects as positive effects of the drug. There is nothing wrong with this and may improve compliance to therapy.
True response requires a modification of electrical flow through neurons in various brain structures. This adaptation (upregulation of some receptors and downregulation of others) takes time, as the neuronal cell membranes need to envelope and degradate some receptors and insert others into the nerve cell membranes. This is where c-Fos, the inositol pathway, etc. come into play, adjusting calcium levels to modify nerve cell excitability. Other secondary messengers shuttle proteins (receptors) from the nucleus and endoplasmic reticulum (where mRNA is making them due to these different-than-normal signals from membrane receptors created by an extracellular concentration change in one, or probably several of the numerous neurotransmitters effected by antidepressant therapy.
I too, have not read Dr.Jensen's book (and most likely will not - a fault of mine - I try to stick to peer reviewed information to decrease confusion). I have asked several world reknown researchers ( >10) if they have heard of Dr.Jensen and so far none of them has heard of him or his book.
Now, this being said. I think that there is some merit to what it is you say that Dr.Jensen is saying. We all agree that depressive symptomatology is an end result that can result from innumerable possible breakdowns of a variety bodily systems regulating stress and emotion. For simplicity I will use an example of just one a neurotransmitter-regualted breakdown, leading to depression. If you give an SSRI to someone who has a depression caused by a malfunction of norepinephrine, 'initially' you will get immediate and pronounced serotonergic side effects. This does not mean that an SSRI cannot be effective in this sort of depression, it is just that it may take longer to "correct" the electrical flow abnormalities causing the depression. It may make more sense to switch to an NRI antidepressant in these instances, but not always. I believe that Dr.Jensen's 3 day method gives up on a therapy too soon.
I used to think that it was silly to keep a person with OCD on Prozac of months on end, with little effect, but after 6 months the person responded with significant decreases in both obsessions and compulsions. Another instance where I thought it was silly to continue therapy was with a person with severe tardive dyskinesia. This person was place on Clozaril and month by month the dosage increased (to 600mg daily) with no apparent (to me) change in the symptoms. This person could not keep a hat on their head at 5 months. A year and a half later this person is now riding a bike and you would be hard pressed to pick him out in a crowd.
In our "fast food" society we expect instant gratification and results. Medicine, particularily psychiatry, is a far too complex field for this and sometimes we have to force ourselves to wait for results.
John, I truly enjoy your input, don't stop. It is hard to stick to one's guns in an onslaught from the mainstream. You are doing admirably, but until I see some other researchers "prove" that Dr.Jensen's method has merit, I cannot endorse it. Sorry, I am just an incredible skeptic, at heart. On the other hand, in 5 years you may be telling us, "I told you so".
"If the brain were simple enough for us to understand, than we would be too simple to understand it." Dr.E.Pugh (I believe, not positive).
Thanks for the lively debate - Cam.
Posted by Shirley on October 28, 2000, at 11:02:06
In reply to 3Day to 2 Week Responses. Proof, not myth., posted by JohnL on October 28, 2000, at 8:59:45
> …..We conclude
> that a treatment strategy producing a rapid onset often, but not invariably,
> has greater efficacy than a treatment producing a slower onset.John,
In my opinion, this is very similar to what my psychiatrist said. Thanks for the information, I'll read all the articles when I have more time.
This may get answered when I read all the articles but I'm inferring from what you said that it was blind luck that the patients were put on medications that caused rapid improvement. Or was there any mention of how these psychiatrists decided that these medications might work promptly?
Maybe the issue isn't that patients can respond very quickly to medications but how do you get to that point. In other words, were these psychiatrists doing things similar to Dr. Jensen or did they go about it in a different way? I felt you were inferring that it was luck but the other side of the coin is something had to lead them to be believe that they might have success with their experiments.
In summary, maybe the issue for the Dr. Jensens and these psychiatrists is to do more extensive studies that would compare what is the most effective way to pinpoint which medications whould work the quickest. I am sensing that the disagreement is not that there are medications that don't work quickly but what is the best way of finding the ones that do.
Sorry for this rambling post but your message caused me to have this "ah ha" experience. I'm a believer in Dr. Jensen but I also understand why people would want more proof.
Again, thanks for the information and I will take a look.
Shirley
Posted by Shirley on October 28, 2000, at 11:33:41
In reply to Re: 3Day to 2 Week Responses. Proof, not myth. » JohnL, posted by Cam W. on October 28, 2000, at 10:53:08
Cam,
I have tremendous respect for you and have always found your posts to be informative. But I have a different perspective.
Regarding the placebo effect, my psychiatrist specifically said that in his experiences, the patients who responded very rapidly to medication was not the result of a placebo effect because they continued to feel well after 3 days. He felt if it had been a placebo effect, they would have stopped feeling well.
Regarding the patients you mentioned who suddenly did better after being on a medicine for a long time, are there statistics regarding those situations? I'm curious because my psychiatrist also said that people who respond quickly to medications are usually going to have the best response. This conversation came up under another situation and I have never mentioned Dr. Jensen.
Other thoughts - I understand why you're skeptical of Dr. Jensen's work. But you're assuming that the mainstream medical profession is always right. Wasn't it only a few years ago that alot of psychiatrists were saying that withdrawal symptoms from anti depressants didn't exist when we now unfortunately know that it's not the case.
I can't prove that Dr. Jensen is correct because I don't have medical knowledge and expertise to back up what I say. But I can tell you from personal experience that if I had waited a long time for a drug to take affect that was showing no signs of helping, I would have missed an awful lot of work besides having alot of heartache. I just think it's very unreasonable to ask a patient to stay on a drug longer than a week or two if it shows no sign of being helpful and the side effects are intolerable. With all the medicines to choose from, I don't think that's instant gratification, I think that's common sense. Of course, I realize there may be exceptions to this and you certain would know more about this than I do.
Even if these studies were funded by the companies that made the drugs, because of my psychiatrist's statement and Dr. Jensen's work, I think it is very possible that there are drugs that cause quick responses. As I said to John in my response, shouldn't you and other folks in the medical community be focusing on finding valid methods that would be able to pinpoint drugs that would work quicker? Even if you think Dr. Jensen's method is invalid and the studies that John presented are flawed because they were funded by the drug companies (which I would agree with by the way), there are still enough evidence of drugs working quickly that warrants further investigation.
In summary, I am not asking you to endorse Dr. Jensen but to keep an open mind.
Shirley
Posted by allisonm on October 28, 2000, at 12:17:08
In reply to Re: 3Day to 2 Week Responses. Proof, not myth., posted by Shirley on October 28, 2000, at 11:02:06
Shirley,
I'm no expert and medicine is not my field, but I believe that -- depending upon the symptoms -- doctors have fairly specific courses of treatment they try, as well as second and third lines of defense. On Dr. Bob's links page you will find a link for the Harvard Algorithms for depression, bipolar and schizophrenia. The Harvard Algorithm is located at:
http://www.mhc.com/Algorithms/I believe it is written for doctors, but I have answered the series of questions about myself to the best of my ability and found that where I am in my current meds is exactly where I land on the algorithm. You may also choose to look at the flowchart, which shows the overall plan.
I do not believe that doctors pick medication choices "out of a hat" so to speak in trying to treat people. I do not believe that their
choices are so inspecific as to be hit or miss. If a person has depression, it's probably due to a particular chemical imbalance, but there's no way of knowing which one until the different drugs that affect them are tried, one after the other. I think they generally try drugs in a specific order to both find the imbalance and try to rule out the other possible imbalances and eventually come to some hypothesis. From what I can tell, one order seems to be something like SSRIs such as Prozac, Paxil, and Zoloft first, then Effexor or Remeron, then augmentation with lithium or Wellbutrin, maybe tricyclics are somewhere in there and then MAOIs.
Unfortunately in the US, we don't have Reboxetine, an SNRI, as I suspect that because SSRIs were so horrid for me I have an
imbalance having to do with norepinephrine and/or dopamine. The drugs I've taken that have helped the situation affect those two chemicals most.One last thing: When drug companies test these drugs, the FDA requires that they do six-week trials, ie subjects have to take these drugs for six weeks before any conclusions can be made regarding efficacy. I suspect there is a reason for it. Frankly, I wonder why they don't require a longer trial period since most ADs are taken much longer than six weeks.
Also, from my own experience, if I gave up on Wellbutrin in the first two weeks because the side effects were bothersome and I didn't feel particularly better, just wired, then I would not have experienced the true benefits of the drug, which occurred weeks later.
Allison
Posted by JahL on October 28, 2000, at 12:40:59
In reply to Re: Cam, posted by Shirley on October 28, 2000, at 11:33:41
I know it's a small detail but doesn't Jensen actually advocate 5 day trials, dropping to 3-4 days if circumstances (ie desperate patient) dictate so?
I think Jensen's approach is a nice idea but could be a little generalised. 5 days? Promazine & Sulpiride take full effect with me in around 3 hours. My brief remission on Paxil took 17 days to appear. When I tapered into Prozac I had almost full remission in 2 days (didn't last)
In the guy's defence he does make it clear that should his methods fail to yield a robust result quickly, he will revert to standard psychiatry.
If the method is successful (& yes we only have Jensen's word that it is), I personally couldn't give 2 monkeys about the validity of the theory behind it!
I guess we'd all be more convinced were a long-standing Babbler to meet the man & achieve cast-iron success. Any volunteers?! ;-)
Ta,
Jah.
Posted by Shirley on October 28, 2000, at 12:56:40
In reply to Re: 3Day to 2 Week Responses. Proof, not myth. » Shirley, posted by allisonm on October 28, 2000, at 12:17:08
Allison,
Thanks for the link, I'll check it out. You're so right that doctors don't engage in hit or miss trials of medicne and that they do have procedures that they follow. It would have been better for me to have asked "How can they improve their procedures so that patients have a better chance of responding quickly to medicine?
You also bring up an excellent point about the FDA and I agree with you that the trials should be longer. As a result, that makes me realize that I am not exactly consistent in my views and I'm not sure how to reconcile them.
I'm glad the Wellbutrin worked for you. But here's where I'm coming from. When I had foot pain that the Zoloft was clearly causing, my psychiatrist switched me to Celexa.
Unfortunately, I became severely agiatated and thought I was going to die, that is in the figurative sense. My psychiatrist lowered the dose and while it wasn't as severe, it will still pretty intolerable. Maybe the side effect would have disappeared and Celexa would have been wonderful. But frankly, I don't think I would have made it to find out. I went back to the Zoloft and fortunately the foot pain didn't return.
I definately understand your point of view. But I also think if a person feels that a side effect is intolerable, that she/he should be given another option without any hassle. Fortunately, my psychiatrist is very good about this issue when I think other pdocs might not be.
Thanks again for your information.
Shirley
.
Posted by JahL on October 28, 2000, at 13:08:49
In reply to Re: 3Day to 2 Week Responses. Proof, not myth. » Shirley, posted by allisonm on October 28, 2000, at 12:17:08
>
> Shirley,
> I'm no expert and medicine is not my field, but I believe that -- depending upon the symptoms -- doctors have fairly specific courses of treatment they try, as well as second and third lines of defense. On Dr. Bob's links page you will find a link for the Harvard Algorithms for depression, bipolar and schizophrenia.>
> I do not believe that doctors pick medication choices "out of a hat" so to speak in trying to treat people.Allison, you obviously have no experience of English pdocs! I wish someone would hand them an algorithm or something. Anything.
Bereft of ideas themselves, they now allow me to choose whichever AD I like the sound of. However, being confined to ADs (the opposite of Jensen) has meant 15 sodding consecutive monotherapies to no effect!
Despite my psychopharmacological naivety I truly believe that, given the prescription pad, I would stand a far better chance of success than my current pdocs do (tho' granted, I could do myself great harm)
Just letting off steam!
Ta,
Jah.
Posted by Shirley on October 28, 2000, at 13:29:32
In reply to Re: 3Day to 2 Week Responses. Proof, not myth. » Shirley, posted by allisonm on October 28, 2000, at 12:17:08
Allison and others,
For what it's worth, I clicked on the link that was suggested. According to the flow chart, I should have been tried on an tryciclyc (sp?) first. Other appropriate choices were Effexor and Serzone.
My psychiatrist was opposed to trycylics because he thought the side effects were worst than the SSRI's and newer drugs like Effexor and Serzone.
I got a partial response on Serzone but even after increasing it to the maximum, it didn't get any better.Interestingly, this article felt that Serzone wasn't as good as choice for someone in my situation as Effexor. Guess what? Effexor was the next option and it worked better than Serzone.
But it wasn't until I was put on Zoloft and Adderall, that my suicidal ideations vanished permanently.Who knows, maybe if I had been put on the tricyclics, I would have had the same result as I did with Adderall and Zoloft. Since I at least have the shadow syndrome of ADD in addition to major depression and tricyclics are also used for ADD, I definately don't discount the idea that tricyclics would have been a viable option. But then again, maybe since I seem to be in the 1% category on side effects, there were probably extremely valid reasons why my psychiatrist didn't want to prescribe them.
Anyway, I just find it interesting that Zoloft and Adderall were the drugs that permanently ended my suicidal ideations in spite of extreme stress that I have experienced the last few years.
According to Dr. Jensen, Zoloft is the number one drug at stopping suicide attempts. Again, this does not prove anything but I find it an interesting coincidence. But maybe if I had been on the tryciclics that this algorythm suggests, I might not have ever been put on Adderall and Zoloft. Pointless to worry about it and I'm just so grateful that I feel good now.Shirley
Posted by allisonm on October 28, 2000, at 13:36:01
In reply to Re: Allison, posted by Shirley on October 28, 2000, at 12:56:40
Shirley,
I absolutely agree with you re' side effects. My doctor first put me on Zoloft because I wouldn't take Prozac. I didn't even finish the sample he gave me, which I think was to last a week. Then he tried me on Effexor XR. I held on longer, but eventually called him in the middle of the day at work saying I couldn't stand it anymore. The Wellbutrin side effects were not as bad, I don't think. Frankly, I'm not sure I'm sure anymore. Maybe by the time I got to the Wellbutrin, I was willing to ride it out awhile longer. This occasionally makes me wonder whether I missed something with Zoloft and Effexor. That said, with so many drugs out there, I don't think I want to try them again.
Posted by Bradley on October 28, 2000, at 15:11:28
In reply to Re: 3Day to 2 Week Responses. Proof, not myth. » JohnL, posted by Cam W. on October 28, 2000, at 10:53:08
Clearly stated on every label of every AD says that the mode of action is unknown. Sure there are a lot of theories. I don't think its wise to accept one until it has proof. The imbalance of nuerotransmitter theory has been around at least 50 years and still is unproven.
Posted by SLS on October 28, 2000, at 19:05:04
In reply to 3Day to 2 Week Responses. Proof, not myth., posted by JohnL on October 28, 2000, at 8:59:45
3-4 (+1) day trials make a whole lot more sense to me than do two week trials. If Jensen is on to something here, and he very well might be, then I believe his protocol is to be followed as he has written it. I'll leave some brainstorming to others to offer thoughts as to why this is probably so. I may find much of what Dr. Jensen has to say to be ludicrous and obviously without scientific foundation, but he is no dummy. 3-4 day trials means 3-4 day trials, not two week trials.That some people begin to improve before the end of the second week is not, and never has been, a "myth". There is no revelation being uncovered here. I have a hard time understanding why this issue has been perceived as an either-or affair. I have not had too difficult a time recognizing this phenomenon. I responded within an hour of my first dose of Effexor. I responded within 3 hours of my first dose of Dexedrine. I gleaned improvements from Dexedrine and Parlodel for the first three days after adding them to Parnate. A month ago, I experienced a teasingly significant antidepressant effect from Parnate + desipramine on days 5-7 that has since faded. I have experienced the same thing with Parnate by itself. Same with Lamictal. I tend to respond (if you can call it that) a week sooner now than when I was a "virgin". So, I guess I have been fortunate enough to have had this great revelation as early as 17 years ago. Duh.
Medicine, particularly psychiatric medicine, is a clinical discipline. If you are already at two weeks and nothing good and nothing bad is happening, you go one more. It is as simple as that.
Does anyone disagree?
I believe most psychiatrists will attest to the fact that not only have they seen atypical robust responses within a week, but that they have also in a great many cases observed a "lightening" of depressive symptoms that can be seen at about the 6-day mark. It is measurable if it is the practice of the physician to measure it. However, this is usually not apparent to the patient because it is so subtle. In these instances, the patient may not feel substantially better to report such for another two weeks. It's good that such a trial would be allowed to continue beyond 14 days.
Interestingly, in opposition to the inferences of the study cited, the older psychopharmacologists would tell me that the slower and more gradual the course of improvement, the more likely it was to "stick". But they had not thought to use strategies such as the addition of pindolol to SSRIs (of debatable efficacy) to hasten an improvement. Maybe they were 180 degrees wrong. It just so happens that it was true for me. Like JohnL always says, we are all different. 3 days, 7 days, two weeks, six weeks.
As I have said in another thread, a 3-4 day trial protocol for screening for effective antidepressants is an exciting idea that would revolutionize psychiatry if it were true. Hopefully, we can get an answer on this soon. There are reasons why I NEVER said in previous posts that it wasn't true (at least not that I can recall). It has had some appeal to me. From my own experiences with medications and those some of the expert clinicians who I have spoken to, the phenomenon that I think Jensen may be focusing on falls within his time-frame. I think it is presumptuous to be so cavalier as to modify it without understanding it.
As far as the aggressive post that I regret submitting in the previous thread is concerned (I really need to start counting to ten), well, I still see what I see. I can't help it. I'll let it go for now.
JohnL has a much better feel for the character and behaviors of various drugs than do I, has greater exposure to creative polypharmacy than do I, and has successfully helped many more people than have I.
- Scott
Posted by AndrewB on October 28, 2000, at 21:55:33
In reply to Re: 3Day to 2 Week Responses. Proof, not myth. » JohnL, posted by Cam W. on October 28, 2000, at 10:53:08
> True response requires a modification of electrical flow through neurons in various brain structures. This adaptation (upregulation of some receptors and downregulation of others) takes time, as the neuronal cell membranes need to envelope and degradate some receptors and insert others into the nerve cell membranes. This is where c-Fos, the inositol pathway, etc. come into play, adjusting calcium levels to modify nerve cell excitability. Other secondary messengers shuttle proteins (receptors) from the nucleus and endoplasmic reticulum (where mRNA is making them due to these different-than-normal signals from membrane receptors created by an extracellular concentration change in one, or probably several of the numerous neurotransmitters effected by antidepressant therapy.
>
Cam,Thank you again for sharing your knowledge with us. I have a few questions I was hoping you could take the time to clear up for me concerning an explanation of the different ways in which neurotransmitters systems may exhibit dysfunction which can lead to depression.
Some background first so you know where I am coming from. Scott was nice enough to send me an abstract recently which indicates that SSRIs tend to be effective in people who have low dopamine post-synaptic receptor responsivity, while SSRIs tend to be ineffective in those with normal or supersensitive dopamine receptors. The study concluded that SSRIs work to ameliorate depression via increasing (upregulating) dopamine receptor sensitivity and therefore only work in those with subnormal (dysfunctional) receptor sensitivity.
Let us for the moment accept this conclusion and also note that some people with depression don’t respond to SSRIs but respond to other meds that clearly function by increasing dopamine transmission. For example, amisulpride has been shown to relieve depression in many where SSRIs have failed. Amisulpride clearly works by antagonizing dopamine pre-synaptic autoreceptors.
This seems to indicate that those helped by amisulpride like those helped by SSRIs suffer from dopaminergic hypofunction, but the specific type of the neurotransmitter dysfunction was different in the two groups. The SSRI group had low post-synaptic dopamine receptor sensitivity while the amisulpride group had some other problem (For example, maybe the amisulpride group had autoreceptors that were overactive and broke down too much dopamine and overly inhibited the release of dopamine).
Anyway, here are the questions I hope you can help me with Cam:
1) What happens specifically when an SSRI upregulates receptors. When you referred to new receptors being inserted into nerve cell membranes and calcium levels being adjusted through intermediary mechanisms to modify nerve cell excitability, does this apply to the changes that take place to create upregulation. Can you expand on this?
2) What other types of neurotransmitter system dysfunctions are you aware up (besides low post-synaptic receptor sensitivity) that could cause depression. On a related note, are you aware of what specific mechanisms would be responsible for the excess degradation (destruction) of dopamine (or serotonin if you are more familiar with that system).
With respect and gratitude,
AndrewB
Posted by Sandi* Pantalon on October 28, 2000, at 22:47:44
In reply to Any volunteers??, posted by JahL on October 28, 2000, at 12:40:59
I'd volunteer in a millisecond!
If only I could find a combination of (legal) drugs, that could make me feel as good as I did when I was from ages 17 to 30...
...I'm 41 now, and I just don't think I'm supposed to feel THIS BAD while taking various combinations of medications - not to mention HOW BAD I felt BEFORE I took them !
I feel like I'm running out of time to enjoy my life. I've been battling the Big D for too long now - and I've been losing ground the past 7 years.
I just want to FEEL GOOD in my brain !
If I had the money to make an appointment and fly to California for treatment, I'd go in an instant. No hesitation. No worries...
...just hope for what future I have left as a happy, functioning person.
Sandi*
Posted by danf on October 28, 2000, at 22:52:16
In reply to Re: Qs for CamW, posted by AndrewB on October 28, 2000, at 21:55:33
not cam but will add something about neurons & transmitters.
Depression appears to be an abnormal neurological pattern. It is not just a low level of serotonin receptor sensitivity. the system is more complex than that.
however just using neurosynaptic theory as a basis, one has the choices of:
decreased transmitter ( decreased release )
decreased total transmitter available for release
decreased # of transmitter receptors
some blockage of available transmitter receptors by other chemicals
a too rapid uptake of released transmitter
some abnormality of transmitter receptors so normal levels of transmitter are less effectiveAn effective med could work on any of these areas, however, the brain has an autoregulation that tends to compensate for any changes & go back to it's prior level of function. This applies to any neurotransmitter.
Effective meds tend to maintain changes over a period of time.
There are also excitatory & inhibitory nerve pathways that make the nerve ending more or less sensitive to any or to only some transmitters.
Ion levels of Na, K, Ca, Mg, Po, & others also play a role in membrane nerve /sensitivity.
To make this even more complex, there are millions of nerve pathways.
Posted by Cam W. on October 28, 2000, at 23:59:40
In reply to Re: Qs for CamW, posted by AndrewB on October 28, 2000, at 21:55:33
Andrew - I will answer your question (I have printed it off), but please give me a week or so. I too, would be interested in a detailed up-to-date answer. These are the kinds of things I like to think about in the car, on the way home from work (God, I need a life). To give a detailed, hopefully comprehensive, answer, I will need to find a few good journal articles that I have on the subject.
Unfortunately, my inability to say no has me fairly busy, now. I have to finish putting together a presentation for Tuesday. I have to write an article for the Canadian Mental Health Association's newsletter (I forgot about it and the deadline is Nov.6). I also have 2 more presentations to prepare and give before the end of November. AND I have a to attend Edmonton Schizoprenia 2000 Conference on Thusday and Friday of this week.
I will try to answer the questions, but give me a little time to put together a proper answer, one that I think the questions deserve. - Cam
Posted by JohnL on October 29, 2000, at 5:22:15
In reply to Re: 3Day to 2 Week Responses. Proof, not myth. » JohnL, posted by Cam W. on October 28, 2000, at 10:53:08
Hi Cam,
Thank you for you response. I hadn't even thought about who sponsored the studies. Good observation. After pondering the concept, I have to wonder if it really changes anything significantly? I don't think it does, but I could certainly be wrong. Maybe I'm too naive, but it just seems to me double blind is double blind, no matter who's cutting the payroll check. There are no ifs, ands, or buts about it. That's the whole purpose of double blind, right?I think sponsorhip bias can skew the conclusions of a study one way or the other, but they can't significantly skew the actual recorded events during a study. Am I wrong? For example the 17 out of 26 people who showed some response within 3 days, are the physicians liars? Did they just make those numbers up? I can see some of those responders being placebo, some being misinterpreted side effects, but certainly some were authentic. Just based on what I've seen happen in real life, I would guess it's a significant some who were authentic. There's too much scientific and anecdotal evidence to suggest otherwise.
What confuses me, and probably explains why I am naive and all-trusting when I go to read something in reputable print, is that I don't know the difference between peer reviewed and non peer reviewed. I'm not sure where to draw the line? I figure if it ends up in Journal of Psychiatry or whatever, it had to jump through a lot of hoops to get there? Space is real limited and they don't have room or profit potential with junk?
I usually look at it this way. If it's double blind with less than 100 participants, it's note worthy but not conclusive. If it's double blind with at least 100 participants, it's very reliable. If it's double blind with several hundred or more participants, it's solidly reliable. Whoever is cutting the payroll check might influence the conclusions of the author, but can't change the events that took place during the study. I know I'm overlooking something. What am I overlooking? I'm just trying to pinpoint what, if anything, could be so grossly out of line in the 24ish studies I found in just an hour that show evidence of patients responding in a few days to two weeks. Where can I find evidence of equal weight that shows these phenomenon didn't, or don't, happen?
Confused and naive I guess.
John
Posted by coral on October 29, 2000, at 6:44:22
In reply to Re: Cam - Peer reviewed vs non peer? Reliable?, posted by JohnL on October 29, 2000, at 5:22:15
As I understand it, part of this debate is how long it takes the brain to respond. We know, in certain circumstances, the brain can respond with the speed of a lightning strike. In some people, it only takes one "hit" of crack cocaine for the person to become addicted. (NOT that I'm advocating crack cocaine - just commenting.)
Posted by Cam W. on October 29, 2000, at 10:55:56
In reply to Re: Cam - Peer reviewed vs non peer? Reliable?, posted by JohnL on October 29, 2000, at 5:22:15
John -
It makes a HUGE difference as to who is paying for the study. Because of this being such a litigous society, most clinical trials are like Wonder Bread - homogenous, but lacking substance.
Clinical trials contain results from right-handed white males, 25 - 50 years, who have no comorbid disorders, do not drink to excess or do drugs, and who can be talked into continuing to take a drug, no matter how bad the side effects are.A guy that I know socially was in a drug trial for a new heart drug. He came to me and said that this drug he was taking was causing him to act "goofy", gave him headaches, and made him pee his bed every night. He had talked to his doc about this and the doc said the trial only last 8 more weeks (12 week trial) and to put up with the side effects, in the name of science. It is one of the only times I have told someone that maybe they should find another doctor (there was also more involved, including the doc being paid for each patient he could keep in the trial).
As for randomized, double-blind, placebo-controlled trials; do they really exist? It has been found that blinded researchers and even saavy guinea pigs (..er, test subjects) can tell, with a greater liklihood than chance, if they were taking a placebo or the drug. This can be suggested by the side effects profile or the action of the drug (eg How would you design a double-blind, placebo-controlled study of LSD?). Using an active placebo (eg like atropine in LSD studies) can help, but are not perfect. Using a placebo and an active comparator (eg a TCA in a SSRI study) can also help but is not perfect, either. I know one guy who was in a Seroquel study and was given Haldol. He knew this because he had tried all the different antipsychotics several times. He knew how each "felt". He even told me he was taking Haldol. I looked into it and after he had dropped out and the seal was broken, indeed, he was taking Haldol. Perhaps this treatment resistant guy would be a great teat subject (non-compliant, abuses a variety of street drugs, has very developed delusional systems, will go out of his way to help you, and is one of the most honest, reliable, down-to-earth people that I know). This gentleman (who is truly a gentle man) needs to receive his meds daily because he cannot trust himself not to take a week's worth of meds in 1 or 2 day and is floridly psychotic 24/7. Help HIM, drug companies!
Perhaps you can't skew clinical results, but you can fudge as to what they are saying. For example, I saw the following in an article about mirtazapine: "it has the added advantage over other antidepressants of increasing appetite - especially good in wasting diseases - and causing sedation - especially good for insomnia". Also, studies do not seem to be funded more than 6 weeks in many cases. Hell, most drugs don't show full effect that quickly (eg OCD cases). So, if you look at the product monograph of Effexor you will see that the top 5 side effects (nausea, headache, somnolence, dry mouth and dizziness) are all start-up side effects and usually disappear within a couple of weeks. Sexual dysfunction didn't crack the top ten, nor did weight gain; two side effects that do often appear after 2 or 3 months of taking the drug. The PDR (Physician's Desk Reference - US) and the CPS (Compendium of Pharmaceuticals and Specialties - CDN) are filled with drug monographs that read like lawyers' documents, written by lawyers for lawyers.
What a clinical trial can show is gross problems that can happen when taking the drug (eg heart problems in many taking sertindole) or it's relative effectiveness versus other similar clinically tested drugs. Naturalistic studies have to be done, including tens of thousands of people with the disorder. Many of these "real world" people smoke pot or crack, drink to excess on occasion, are female, have congestive heart failure (or other comorbid disorder). Let's see how these drugs do in the real world, head-to-head against it's competition.
Early responders to drugs which usually have a delayed actions in most other people is somewhat of a quandry. Many are placebo effect, a result of actually doing something about your illness or problems, but not all. In many other cases early response is mistaken for secondary side effects (anticholinergic and antihistaminergic side effects of TCAs). These secondary effects could be enhanced to look like drug effects, depeneding upon that person's brain's chenical mix (eg giving an SSRI to someone with noradrenergic overload may decrease some of the NE caused effects, thus the person seems to be responding to the drug. This could change in a week or two as the SSRI begins to change that internal mix). You have to wait with any psychoactive drug, because the body is going to try to overcome the effects of the drug by changing concentrations of neurotransmitters and their receptors in different parts of the brain. Every person's internal environment is different, but when a vast majority of people have a delayed response in treating a disorder, you look to other causes for improvement (other than drug effect).
As for your physicians as liars comment: why should they be any different from you and me? These researchers are trying to pay mortgages, "keep up with the Jones", and carve a niche in the scientific framework with their name etched on it. Most negative studies that are supported by the drug company aren't reported and the researcher isn't the first asked to do the next trial. Results from trials are in many cases subjective. The concrete results can also be manipulated. For example, what is the criteria for response (usually a 50% reduction in HAM-D scores for AD testing). This 50% reduction in HAM-D scores doesn't say how many of the residual depressive symptoms are remaining. Someone who is severely depressed at onset of therapy may still be significantly depressed with a 50% reduction in their symptoms.
Researchers are becoming very deft at reporting what both the drug company and the research journal want to hear. Look at the fine print of the journal article, not only for who's paying the bills, but also how much trouble it was getting the article printed. Look for the following dates in the fine print. Date received, date accepted (after changes made) and date published.Some articles aren't published until over a year after acceptance. This, in my opinion, reduces the worth and applicability of the study. It shouldn't, but it does. I figure that if Dr.Stahl (J Clin Psych) or Dr.Andreasen (Am J Psych) added this study "to fill space", a year after it was accepted, this study must not be as important as others in the same journal.
You actually posed these questions to me at a time when I have been reading and highlighting about 10 journal articles a day. I am quickly becoming jaded to not only the whole drug approval process, but also the elegantly written drug commercials in the form of journal articles.
Anyway, before I get myself in trouble with the drug companies and never get another speaking engagement (yes, I'm a drug company whore, but I try to minimize my worship of any drug), I think I will stop here.
Scientific method isn't perfect, but until someone can show us a better way of proving things to be objectively true (sorry, dreaming again), scientific method is all we have. People will always find ways to make their product look better than their competitor's (eg Vick's inhalers make you "feel" clearer, they don't make you clearer).
1) If it sounds to good to be true, it is.
2) Believe nothing of what you hear and only some of what you see.
3) Never believe that someone has "your" best interest in mind, particularily if it involves the output of money.One of my longer rants - Cam
Posted by Cam W. on October 29, 2000, at 10:59:03
In reply to Re: brain time, posted by coral on October 29, 2000, at 6:44:22
> As I understand it, part of this debate is how long it takes the brain to respond. We know, in certain circumstances, the brain can respond with the speed of a lightning strike. In some people, it only takes one "hit" of crack cocaine for the person to become addicted. (NOT that I'm advocating crack cocaine - just commenting.)
•Coral - The addiction after one hit of crack is psychological in nature; the physical addiction (changes in brain chemistry) comes with repeated use.
just my 2˘ - Cam
Posted by JohnL on October 30, 2000, at 5:12:39
In reply to Re: Cam - Peer reviewed vs non peer? Reliable? » JohnL, posted by Cam W. on October 29, 2000, at 10:55:56
Cam,
Thank you for the time you put into your response. I know how busy you are and I greatly appreciated the reading. Sometimes I look at my own posts and I think, "Darn, that's too long, nobody's going to read that", and then I edit the heck out of it just to make it shorter. I lose valuable points in the name of readability. But with your post, as long as it was, it wasn't long enough! Thoroughly enjoyed ll of it. I'm glad I caught you in a writing mood. Thank you.
As a general overall comment, I would say I now find it difficult to trust anyone in psychiatry. Geez. I mean, you're right, everyone is human, everyone has an agenda, and everyone has to pay their bills. As long as humans are involved, objectivity will always be questionable I guess. I still feel though that even though results of studies can be skewed in the whole process, the actual recorded events of the studies can't. Pertaining to this topic of rapid response, I think some can be explained by placebo, some by misinterpreted side effects, but some are authentic. Set clinical studies aside, I've just seen it in real life enough to take notice. That's all. The ones I witnessed, and the ones where witnesses here at this board came forth to describe, were not placebo or side effects.
I do believe many intricate changes in the brain take place after initiating medication. It's not as simple as saying someone's serotonin was low. But I also believe that sometimes the whole process does not have to occur for the patient to feel better. I believe increasing serotonin sets into motion a whole lot of chemical changes in the brain, in a chain reaction. I believe increasing dopamine does the same thing, except that it primarily affects a different set of pathways of chemical reactions, and may only slightly overlap into the serotonin one, and at a different point in that chain of reactions. Likewise, increasing norepinephrine will set into motion a distinctly different set of chain reacions, which at some point may also overlap into the same ones as serotonin and dopamine, but farther down the chain. Because I believe this, I also believe the choice of medication can and does influence the speed to response. For example, if some link in the serotonin chain is awry and is basically at fault for a person's symptoms, a serotonin medication will get around to correcting that problem sooner than a norepinephrine or dopamine medication. Simply because that link in the chain wasn't as far away as it was in the norepinephrine or dopamine chain. And thus a quicker response. In any random population of patients, there are always some who get better a lot faster than others. I think that is explained by the medication affecting the correct chain of reactions, and not having to wait for a longer domino effect that eventually gets around to the real culprit chain, if it ever does. Fewer dominos to knock down, so to speak. Not a scientific view, but that's my interpretation.
To further complicate the matter, each person has unique genes and unique wiring. Things in the brain might be intertwined and arranged differently than someone else's, amongst the millions of neurons and such. And to complicate it even more still, not all medications will have the same binding potential from one person to the next. Thus not only is choosing the correct medication for the correct chain of events important, but choosing one with the correct binding potential for that unique individual is also important. Whatever medication does all that is a superior match in my definition. Unfortunately the only way to find the medication that does all that is to try and compare different medicines. The superior match will make itself known, and there is no doubt when it's found. I've just seen it happen too many times to discount it as fluke.
I think we all tend to see what we want to see, or see only what we're looking for. That's natural for humans I think. Imagine you and me taking a hike through a densely wooded forest in Canada. You might take notice of the different types trees, because you just happen to be into trees and you've been thinking about firewood for the winter lately. Meanwhile, I didn't really notice one tree from another, they were all just trees to me. But I noticed the groundcover we were walking on. It was Brunswick blueberries which only grow several inches tall. I'm into fruit gardening, so I noticed these right away. Everything was there for both of us to see equally, but we each picked out different things depending on what our interests and desires were. And thus the subjectivity of humans you mentioned in your post. And thus in psychiatry, no matter what kind of evidence presents itself, you will see what fits your world and I will see what fits mine. In a perfect world, we would all have innocent eyes to see it all, and not just parts.
> 1) If it sounds to good to be true, it is.
....probably, but not always. (Reminds me of a certain psychiatry book. Test and compare medications for a week each to find a favorite, or to elimate a whole class. Not as good as it sounds. Ever tried taking ABC med for a week, stop, wait, then take XYZ med for a week, stop, wait, then the next? It sounds good, and it works, but believe me, it aint no picnic!) :-)> 2) Believe nothing of what you hear and only some of what you see.
....True, at least up to the point you have reason to believe one way or the other. I want evidence to support or refute what I see and hear before adopting a general conclusion. (Reminds me of how I was going to take such pleasure out of critiquing a certain psychiatry book because it sounded too good to be true. The only problem was, in all my years I couldn't find the faults I was sure existed. Damn.)> 3) Never believe that someone has "your" best interest in mind, particularily if it involves the output of money.
....Sometimes. (Reminds me of my local psychiatrist. He sincerely had my best interest in mind at all times. Only after I had received personal customized care did he send the bill. Pristine service, no hint of anything except my best interests. In contrast to an earlier local psychiatrist who seemed to care not at all that Serzone was making me more depressed as the weeks went by. She just wanted me to schedule yet another appointment and pay her yet another $80 for a worthless 15 minutes that had nothing to with my best interests, while the whole time I'm pondering how I wish I would be dead.)
>
> One of my longer rants - Cam
....Me too. :-) - John
Posted by shellie on October 31, 2000, at 20:53:57
In reply to Re: Cam , posted by JohnL on October 30, 2000, at 5:12:39
> John, did you end up on adrafinil and amisulpride as a direct result of drug trials you did with Dr. Jenson, or did you just use the methodology of Dr. Jenson to continue trying new drugs. Just curious. Thanks. Shelley
Posted by JohnL on November 1, 2000, at 3:44:11
In reply to Re:your progression to your present drug combo » JohnL, posted by shellie on October 31, 2000, at 20:53:57
> > John, did you end up on adrafinil and amisulpride as a direct result of drug trials you did with Dr. Jenson, or did you just use the methodology of Dr. Jenson to continue trying new drugs. Just curious. Thanks. Shelley
Shellie,
At one time Dr Jensen did help me out. Here is a progression of how it went.He always starts with a full physical exam and blood tests. I had to do this, and then have my GP fax him the results before anything else could be done.
Next was the phone consultation. For an hour he asked me lots of questions. When finished, he faxed my GP an outline of treatments I could try, with his reasonings of why he thought they should be tried. Mostly it was technical drug related chemistry stuff.
Next I had to see my GP to review the consultation and the faxed recommendations. Jensen gave me a lot of leeway. He encourages the patient to be involved in the decision making process if they so desire. He believes it is therapeutic for the patient to have ownership in their own treatment, if they want to. I was given three choices. 1)Do short trials of three SSRIs I had not tried. He gave me room here to do 5 days each, 2 weeks each, or whatever. The choice was up to me. For him 5 days was sufficient, but it was up to me. 2)Try 3 different antipsychotics. 3)Try Ritalin and Adderall.
After all this had been done, I was to set up another phone consultation. But it didn't work out that way, and here's why. My GP insisted that I see him after each drug trial. Jensen made it clear I was to try one drug, wash it out for a couple days, try another, and so on, until I had exhausted each drug in that class. I was to keep notes of mood changes, side effects, etc. But my GP screwed it all up. He wanted me to see him after each drug trial AND consult with Jensen after each drug trial. So, I was looking at trying about 7 drugs and having to pay two doctors for visits between each drug? Yikes! That is not how it was intended to work. But that's how my GP wanted it.
So I had to think real hard about it. It seemed to me that basically what Jensen wanted to do with me was explore classes of drugs I hadn't tried. In a nutshell that explains the whole point of his method...explore all options, don't rule out any. So then I thought, ya know, I can get almost all of these drugs myself from overseas mailorder pharmacies. The only ones I can't get are the stimulants. So I opted to do those with my GP under his rules. During that process, Ritalin was the tip-off I had been looking for. It gave me all the clues I needed to know that whatever was wrong in my brain, it had little to do with the serotonin pathways, but a lot to do with something in the NE/dopamine pathways. Ritalin was too addicting for me, but at least I now knew where to look...NE/dopamine drugs.
So then I just started making a list of such drugs I could get on my own, and completely bypass the enormous expense of having to pay two doctors simultaneously and frequently. One of them happened to be Adrafinil. Another happened to be Amisulpride. Since I was given the choice, I figured I would go with 2 weeks or so instead of 5 days. But with both drugs, I knew the first day I was on to something good. There were no side effects to speak of, and I felt a little bit better almost right away. This was exactly what Jensen would have been looking for, had I still been under his treatment. Later I experimented by combining the two and was real happy with that.
At that point my search was over. So basically, his direct guidance provided me the roadmap to get where I wanted to go. One of the drugs on his trial-list for me was Ritalin...it provided good strong clues. Another was Zyprexa...it also provided good strong clues, though too sedating for me. Adrafinil and Amisulpride are just fine-tuned variations of those two drugs that worked well for me but had their problems of side effects or addiction. My only regret is that Jensen wasn't present to see the good results his roadmap led to. But I'm sure he sees it all the time. Nothing new.
It's really just as simple as trying drugs from various classes, even if there is little or no clinical justification for trying them. Very often excellent results are discovered that way. At first Jensen noticed these things by accident. Now he looks for them on purpose. To think that somehow antidepressants alone can cover the entire spectrum of depression brain chemistries seems unreasonable to me.
John
Posted by shellie on November 1, 2000, at 9:12:37
In reply to Re: Shellie - How the method worked for me., posted by JohnL on November 1, 2000, at 3:44:11
.
This is the end of the thread.
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