![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 8 of 8. This is the beginning of the thread.
Posted by SLS on January 9, 2001, at 18:48:11
Please indulge me.
I have decided to post this letter that I wrote as a personal correspondence to a colleague of mine.Balance.
Spectrum.
Heterogeneity.
-----------------------------------------------------------
I have begun to respond to the addition of Risperdal to my Parnate, desipramine, and Lamictal. The response became apparent just two days ago. Three days ago, I was on the phone with my doctor complaining that things were going nowhere, but he urged me to continue. I'm glad I didn't stop at the four-week mark. It took six. However, I did experience a transient improvement during the first week that pretty much disappeared. Someone else has had the same thing happen to her. She is sticking with it. I bet she eventually responds. I hope so.Biology is a beautiful and frustrating thing to study.
I am becoming more and more attracted to finding some way of utilizing the transient "blip" response that occurs with some people within the first 5 days of beginning an antidepressant to improve treatment algorithms. However, the number of days may be dependent upon the pharmacokinetics of the specific drug, as it would take longer to build up to the threshold concentration that would induce such an early blip response. I imagine that there are creative ways to circumvent this variable. One study I came across used the administration of loading dosages for two consecutive days, followed by several days in which no drug was administered. The idea is that this will produce a differential metabolic profile to be used to predict eventual response. Sound familiar? I have been attracted to Jensen's protocol all along. Unfortunately, xxxxx took the liberty of extending his screening trials to two weeks, which completely sabotages the algorithm.
Several problems:1. It is well documented that the more severe the depression, the longer it takes to respond to a drug that will ultimately foster a long-term response. 4 - 6 weeks minimum. So, what do you do in such cases, especially when a blip response does not occur?
Of course, it can be argued that if one were to continue screening for different drugs, perhaps a blip response would be found.
2. Treatment-resistance. When reviewing naturalistically a population of depressed individuals, many subjects are found to respond to only one drug that never evidenced a blip response. So now you test all of the antidepressants, taking each for 5 days. No one drug will have provoked the response that would allow for its choice as a drug to be tried first. Ten drugs take 2 months. Time totally wasted. Now you have to start all over again using the more traditional guidelines. These people will have been missed.
3. Polypharmacy. When employed as the only clinical tool, the 5-day screening trial assumes that a single drug will produce a blip response. However, there are many, many people for whom there is absolutely no sign of improvement with monotherapy, and who will only respond to the addition of a second or a third drug. Again, this is 2 - 3 months wasted. Many will be missed.
4. Even if a blip response occurs, it may still 4 - 6 weeks to titrate and establish the individual's threshold dosage for response, whereupon, 2 more weeks are necessary. Often, side effects limit the rate at which dosages can be increased. Sure, it might only take two weeks of treatment with the right drug at the right dosage to elicit a response. But how do you establish in advance the right dosage so as to "start the clock". Perhaps some sort of evaluation of various biological parameters can be measured upon the initiation of treatment or after a test loading dose that would serve to predict the eventual minimum effective dosage.
By the way the term "blip" is not mine. Believe it or not, it was part of the clinical jargon used at the NIMH when I was there in 1992. Again, that such things occur and are viewed as favorable prognosticators is not much of a revelation to me. I am only guessing that it is this blip phenomenon that Dr. Jensen has focused on and is using to his advantage. I think Jensen's premise deserves merit based upon what I have learned. However, inappropriate and illogical use of it is dangerously counterproductive.Oh yeah. It has been recognized for quite some time that early responders (2 - 3 weeks) generally fair better in the long-term. This is not a particularly powerful revelation to me either. However, this is a sort of hindsight statistical observation that I'm not sure would be appropriate to act upon when deciding whether or not to continue a drug regimen that takes 4 weeks to produce a substantial improvement.
I have found it difficult to represent this type of balanced perspective regarding these issues as there is a tendency for some people on PB to think in either/or terms. Perhaps I should post this letter.
* Anyway, here is the abstract. It is unrelated to all of the garbage I wrote above.
See you soon.Sincerely,
Scott
-------------------------------------------------------------------
4: Biol Psychiatry 2000 Oct 15;48(8):830-43Regional metabolic effects of fluoxetine in major depression:
serial changes and relationship to clinical response.Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis
S, Jerabek PAResearch Imaging Center, The University of Texas Health Science
Center at San Antonio, (HSM, SKB, RKM, SM, PAJ), San Antonio,
Texas, USA.[Medline record in process]
Background: Treatment of major depression with antidepressants is
generally associated with a delay in onset of clinical response.
Functional brain correlates of this phenomenon have not been
previously characterized.Methods: Time course of changes in brain
glucose metabolism were measured using positron emission tomography
in hospitalized unipolar depressed patients treated with
fluoxetine. Time-specific and response-specific effects were
examined at 1 and 6 weeks of treatment.Results: Changes were seen
over time, and characterized by three distinct patterns: 1) common
changes at 1 and 6 weeks, 2) reversal of the 1-week pattern at 6
weeks, and 3) unique changes seen only after chronic treatment.
Fluoxetine responders and nonresponders, similar at 1 week, were
differentiated by their 6-week pattern. Clinical improvement was
uniquely associated with limbic and striatal decreases (subgenual
cingulate, hippocampus, insula, and pallidum) and brain stem and
dorsal cortical increases (prefrontal, parietal, anterior, and
posterior cingulate). Failed response was associated with a
persistent 1-week pattern and absence of either subgenual cingulate
or prefrontal changes.Conclusions: Chronic treatment and clinical
response to fluoxetine was associated with a reciprocal pattern of
subcortical and limbic decreases and cortical increases. Reversal
in the week-1 pattern at 6 weeks suggests a process of adaptation
in specific brain regions over time in response to sustained
serotonin reuptake inhibition. The inverse patterns in responders
and nonresponders also suggests that failure to induce these
adaptive changes may underlie treatment nonresponse.PMID: 11063978, UI: 20520130
Posted by JohnL on January 10, 2001, at 6:17:55
In reply to Stuff., posted by SLS on January 9, 2001, at 18:48:11
Hi Scott,
Hey I like this post! Cool work you did. I especially like the term 'blip'. I wish I had thought of it first!Most people I think don't give enough weight to the blip effect. I think it bears significance. Dr Martin Jensen uses the blip method in 5 day trials to screen for two things: 1)superior drug matches; 2)a better understanding of the underlying chemistry of the particular patient. XXXX modified it to his/her own hybrid method by using two weeks as the parameter. My favorite old timer psychiatrist used the blip method, though I don't think he consciously thought of it that way. You could modify it to come up with your own hybrid.
John
Posted by MarkinBoston on January 10, 2001, at 13:18:12
In reply to Stuff., posted by SLS on January 9, 2001, at 18:48:11
Thanks for the posting.
A couple suggestions on your concerns over time losses in getting to a positive response:
1. The treatment resistant are a minority to begin with, so each subcatagory is yet smaller.
2. My doc, at the signs of 1-2 SSRI non-response will go to multi-drug therapies blanketing what the failed drugs do not affect, and to a high dose in order to elicit the fastest response. The components with intolerable or undesireable side effects as noted while titrating up can be dropped or substituted. Provided a response occurs, eliminating non-contributing drugs (usually starting with the one's least tolerated) then reducing dosage can be done until response declines. Shoot first and ask questions later when finesse' fails.
Posted by JahL on January 10, 2001, at 16:50:14
In reply to Re: Stuff., posted by MarkinBoston on January 10, 2001, at 13:18:12
> 2. My doc, at the signs of 1-2 SSRI non-response will go to multi-drug therapies blanketing what the failed drugs do not affect, and to a high dose in order to elicit the fastest response. The components with intolerable or undesireable side effects as noted while titrating up can be dropped or substituted. Provided a response occurs, eliminating non-contributing drugs (usually starting with the one's least tolerated) then reducing dosage can be done until response declines. Shoot first and ask questions later when finesse' fails.
I like this approach if the patient is informed & consensenting. Particularly if, as in my case, only meds will provide relief from a lifetime of chronic depression (& there are no 'issues' involved).
I only wish this sort of approach (where appropriate) was practised more widely over here in Britain. There's just NO sense of urgency.
Jah.
Posted by JohnL on January 10, 2001, at 18:01:13
In reply to Re: Stuff., posted by JahL on January 10, 2001, at 16:50:14
> > 2. My doc, at the signs of 1-2 SSRI non-response will go to multi-drug therapies blanketing what the failed drugs do not affect, and to a high dose in order to elicit the fastest response. The components with intolerable or undesireable side effects as noted while titrating up can be dropped or substituted. Provided a response occurs, eliminating non-contributing drugs (usually starting with the one's least tolerated) then reducing dosage can be done until response declines. Shoot first and ask questions later when finesse' fails.
>
> I like this approach if the patient is informed & consensenting. Particularly if, as in my case, only meds will provide relief from a lifetime of chronic depression (& there are no 'issues' involved).
>
> I only wish this sort of approach (where appropriate) was practised more widely over here in Britain. There's just NO sense of urgency.
>
> Jah.Yeah Jah, it's not just Britain, but everywhere. I don't understand the complacency of phsycians when dealing with depressed patients. I mean, here take this and hopefully you'll feel better in 6 weeks. What?!? Six weeks? Six hours is long enough, six days seems like an eternity, but six weeks? And it might not even work? You're kidding me, right? Geez. Yikes.
Seriously, 1 out of 10 depressed patients take their own lives. 10%. That doesn't sound too too bad. But 10% is 10 out of 100 people. Or how about 100 out of 1000 people. Yowee. Now it's looking serious. Depression is so bad people literally kill themselves on purpose. Second only to car accidents it is a leading cause of death for teens and early twenties. Depression is major serious stuff and I feel doctors and psychiatrists approach it way too lightly. I've only had the good fortune of knowing two who were very aggressive. With one, if a med didn't show promise in 5 days, forget it. Move on. With the other, his window was in the 2 to 4 week range. Both were very aware that without showing aggressiveness in my treatment, the next time they saw me might be on the obituary page.
And of course chronic depressions like yours and mine are just as harmful, ending lives, ending marriages, ending careers, destroying finances, stopping all progress in life, on and on. Serious stuff that can't wait.
I wish all doctors would attack depression with vigor and a sense of urgency. Because after all, it is an urgent situation. Lots of things have been shown to speed the onset of antidepressants, including benzos and stimulants. I think patients would be much better started off on day one with both an antidepressant and small safe sample packet of Ritalin as well as a small safe sample packet of Xanax. They could take whatever helps them feel better quickest, as needed. Meanwhile, when the antidepressant starts to kick in, then they can withdraw or modify the other drugs. In any case, every possible trick in the book should be used right from day one, in my opinion, not just after someone has been disappointed with one or more drug trials. After all, a hundred out of a thousand of those people are going to be six feet underground by then.
I like the way Mark phrased it, shoot first and ask questions later, something like that.
John
Posted by SLS on January 10, 2001, at 18:10:26
In reply to Re: Stuff., posted by MarkinBoston on January 10, 2001, at 13:18:12
Dear Mark,
> > 1. The treatment resistant are a minority to begin with, so each subcatagory is yet smaller.You are right. I sometimes lose perspective regarding treatment of the general population during their first episode. I have been so focused on treatment-resistant cases, that I often think of them as the reference population.
I don't understand what you mean in the clause, "so each subcatagory is yet smaller".
> > 2. My doc, at the signs of 1-2 SSRI non-response will go to multi-drug therapies blanketing what the failed drugs do not affect, and to a high dose in order to elicit the fastest response. The components with intolerable or undesireable side effects as noted while titrating up can be dropped or substituted. Provided a response occurs, eliminating non-contributing drugs (usually starting with the one's least tolerated) then reducing dosage can be done until response declines. Shoot first and ask questions later when finesse' fails.
> I like this approach if the patient is informed & consensenting. Particularly if, as in my case, only meds will provide relief from a lifetime of chronic depression (& there are no 'issues' involved).
>
> I only wish this sort of approach (where appropriate) was practised more widely over here in Britain. There's just NO sense of urgency.
>
> Jah.
I'm with Jah. I really, really like this approach.Thanks.
- Scott
Posted by MarkinBoston on January 10, 2001, at 19:34:51
In reply to Re: Stuff. , posted by JohnL on January 10, 2001, at 18:01:13
> I wish all doctors would attack depression with vigor and a sense of urgency. Because after all, it is an urgent situation. Lots of things have been shown to speed the onset of antidepressants, including benzos and stimulants. I think patients would be much better started off on day one with both an antidepressant and small safe sample packet of Ritalin as well as a small safe sample packet of Xanax. They could take whatever helps them feel better quickest, as needed. Meanwhile, when the antidepressant starts to kick in, then they can withdraw or modify the other drugs. In any case, every possible trick in the book should be used right from day one, in my opinion, not just after someone has been disappointed with one or more drug trials. After all, a hundred out of a thousand of those people are going to be six feet underground by then.
>
> I like the way Mark phrased it, shoot first and ask questions later, something like that.
> JohnI asked for those adjuncts and got them from doc. There's more: T4&T3 thyroid, testosterone and/or estrogen blocker (for men), and antiglucocorticoid (cortisol antagonist) treatment. They treat just the symptoms of endocrine disruption by depression, but provide quick relief just the same. The last one was encouraged by the NIH in a Jan 2000 PNAS "penis" (Proceedings of the National Academy of Sciences) paper. Testosterone does improve men's mood, except at excess, and lowering estrogen does dull panic (CRF response from a stressor). Getting a script for testosterone was no problem. Convincing a Dr. to manage estrogen levels also was a challenge adding to depression.
Posted by MarkinBoston on January 10, 2001, at 21:16:44
In reply to Re: Stuff., posted by SLS on January 10, 2001, at 18:10:26
> I don't understand what you mean in the clause, "so each subcatagory is yet smaller".Blipers who later respond.
Blipers who don't later respond.
Non-blipers who would have responded.
Non-blipers who don't later respond.are the sub catagories, and you were concerned about "missing" on the middle two exception groups. So, overall, you're helping the vast majority of patients.
As to me and my doc. She and I have had an on again off again relationship for almost 10 years. I go a year or two between major episodes when I start having cognitive and memory problems, stay on high dose Effexor until I can't stand the apathy, sweating, and anorgasmia after I'm "cured". Motivation returns, subtlely anhedonia and dysthymia creep up and some period of job stress or SAD brings on another major. She knows I fall into the repeat customer catagory and am not just calling to say hi, so out comes the full assault. We've talked about staying on meds full time, but it hasn't been attractive until seeing John's cocktail. I'll shift over to it when I tire of Effexor again.I also wish doctors would treat obesity aggressively. The mortality risk is there like depression and should also be aggressively treated. "Eat less, exercise more" is about as helpfull as "think positively" works for us. Pull out some big guns: speed + thyroid + anabolic steroids + a diuretic anti-hypertensive with close management to get someone feeling better and feeling like exercising, while they establish healthier behaviors.
Using the above, without the thyroid to reduce my depression had a pleasant side effect for me. I felt better and got back to my pre-depression exercise habits, increased lean tissue, decreased adipose tissue, and had a net loss of 30 lbs. - in two months. A kick start like that is great, like the adjuncts JohnL mentioned, and not meant to be a long term solution.
With the diet industry at $23B, what doctors have to offer is truely lame. A kick start now and then is far better than the downstream consequences of diabetes, coronary disease, and myriad problems. This is valid preventive medicine like anti hypertensives or statins. Women can take non androgenic anabolic steroids. They are weaker, and the benefit is less.
The bigger problem is the reefer madness type campaign against steroids and diet pills is resulting MD ignorance about proper use of the former group of meds and reluctance to use either. I stumbled upon the MSN dieting chat group and it was 99.9% women, many of whom were >100lbs overweight and many of the 300+ lb. considering stomach stapling despite mortality risks. God, are steroids so bad that major surgical procedures like this are safer and cheaper? Long term success for this surgery were not good either - plenty of women gained the weight back and then some.
Depression with its elevated cortisol and reduced seratonin are risk factors for obesity, hypertension, and arterial disease. Worse, as men age, cortisol and estrogen rise, GH and testosterone decrease, increasing risk for depression and the others. These things can be managed and cost less than hospital admissions. Remember the AMACO transmission ads? "You can pay me now, or you can pay me later," with the implication that later was going to cost much more.
I accepted some weight gain from AD meds as an OK trade-off. I'm less accepting that tradeoff now.
Docs are starting to get more aggressive treating depression. A friend is a resident in Burlington VT. After having seen twice, men in the ER with self-inflicted gunshot wounds, she said she aggressively treats depression now, especially in men.
This is the end of the thread.
Psycho-Babble Medication | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.