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.
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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
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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
poster:SLS
thread:51307
URL: http://www.dr-bob.org/babble/20001231/msgs/51307.html