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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 5 to 29 of 49. Go back in thread:
Posted by Bob on April 24, 2010, at 16:41:52
In reply to Re: Multiple drug exposures and treatment resistence, posted by desolationrower on April 24, 2010, at 16:37:05
Huh? What does this mean?
Posted by bulldog2 on April 24, 2010, at 17:42:59
In reply to Multiple drug exposures and treatment resistence, posted by SLS on April 24, 2010, at 11:53:56
> Yeah. No kidding...
>
> If you are severely ill, what choice do you have?
>
> I had a doctor tell me that I should remain as clean as possible between trials of newly available medications. He was right. The brain must surely change in response to drug exposure. If it didn't, there would be no such thing as an antidepressant response or the phenomenon of poop-out. Why am I no longer responsive to the same treatment I had success with previously? Something must be different.
>
>
> - Scott
>
>
> -------------------------------------------------
>
>
> Neuropsychobiology. 2009;59(4):227-33. Epub 2009 Jul 2.
>
> Tachyphylaxis after repeated antidepressant drug exposure in patients with recurrent major depressive disorder.
>
> Amsterdam JD, Williams D, Michelson D, Adler LA, Dunner DL, Nierenberg AA, Reimherr FW, Schatzberg AF.
>
> Depression Research Unit, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-3309, USA. jamsterd@mail.med.upenn.edu
> Abstract
>
> OBJECTIVE: The aim of this post hoc analysis was to examine whether tachyphylaxis occurs after repeated courses of antidepressant drug therapy. METHOD: 276 patients with major depressive disorder (MDD) were treated with sertraline (150-200 mg daily) for 8 weeks. Patients with persistent MDD after sertraline therapy were randomized to continuation therapy with either sertraline plus atomoxetine (n = 72) or sertraline plus placebo (n = 74) for 8 additional weeks. Logistic regression was used to test the hypothesis that an increase in prior antidepressant drug exposure is associated with a reduced responsiveness to sertraline therapy. RESULTS: The number of prior antidepressant drug exposures was negatively associated with response to initial sertraline therapy (odds ratio = 0.81, p = 0.0035). The odds ratio indicates a 19.9% reduced likelihood of response with each prior antidepressant treatment trial. In contrast, the number of prior antidepressant treatment trials was not associated with response to continuation sertraline plus atomoxetine or sertraline plus placebo therapy. CONCLUSION: This observation supports the hypothesis that tachyphylaxis may develop after repeated antidepressant drug trials. Copyright 2009 S. Karger AG, Basel.
>
> PMID: 19571597 [PubMed - indexed for MEDLINE]Scott
The body learns to recognize a foreign substance and how to break it down quickly and get rid of it.
Also a possibility of homeostasis. Some genetic code to maintain who you are. So as in number one stated above once the invader is recognized and mechanisms are mobizlied to deal with it.Maybe you have strong mechanisms of homeostasis.
Posted by bleauberry on April 24, 2010, at 18:10:06
In reply to Multiple drug exposures and treatment resistence, posted by SLS on April 24, 2010, at 11:53:56
Interesting article, but they don't really get to what really matters...WHY or HOW does it happen? What is happening?
This is probably a topic we have all wondered about over the years. Probably a lot of theories going around. Here are some of mine:
1. As the immune system can eventually recognize and reject a particular molecule, it learns how to do that with the medication molecule.
2. Gene instructions are changed upon first exposure to a drug. They do not revert back to their original baseline after discontinuation of the drug. They remain altered. Reintroduction of that drug would have no effect because the changes already previously happened.
3. In an attempt to maintain homeostasis, the body is very pliable and creative at figuring out how to do that. For example with me, when my adrenals were burned out, my lifelong borderline hyperthyroidism went to borderline hypothyroid in a short timeframe. Since the adrenals couldn't be turned up, the thyroid was instead turned down to match it, so as to be in balance. Low balance, but balance. The body did what it could to adapt to weak adrenals by turning down the volume on everything else.
When we increase serotonin, or whatever, by a mechanism which is not natural, the body does what it can to get that serotonin back down to where instructions say it should be. The genes don't know or care if we are depressed or not, they have instructions to follow. In the attempt, the enzymes that convert tryptophan to serotonin are changed. Serotonin production drops. It doesn't matter that we block reuptake or mao, because there just isn't much there to work with. The body already turned the volume on the neuros way down. Now we need a drug just to keep the levels up at genetic baseline, which happens to be too low and we stay depressed.
Possibly the receptors become sensitized to the artificially increased serotonin, and stay that way. No amount of serotonin will cause them to budge. They have sort-of developed resistance to serotonin, basically rejecting it, ignoring it, rather than receiving it.
4. Biochemical damage. We have no idea what damage the meds do to neurons, genes, dendrites, or receptors. Skeptics claim they are deformed and destroyed, and their numbers and densities are greatly diminished. While fans claim the meds are neuroprotective. I think this needs a lot more research.
5. The genes can be fooled once, but not every time. Perhaps on first exposure to a drug, the genes do change, and opposed to #2 above, the genes do revert back to baseline instructions after discontinuation. But, on followup exposure they now recognize the drug molecule as an imposter. The drug can increase serotonin all it wants to, but the genes this time are saying, "we're up to your tricks this time, and we are not doing all the downstream adaptation stuff you tricked us into last time around".
6. There is an underlying disease or insult, where serotonin (or whatever) is low as a result. Lyme, heavy metals, whatever, anything. Upon the first exposure to a drug, that deficiency is corrected. However, the disease is not corrected. It continues to progress. Later, as the drug is attempted again, the disease has progressed far enough that the drug is not potent enough to do what it did the first time. Or even if it is, there is now more widespread damage well beyond a simple deficiency.
I have a feeling that of all the theories I can muster up, I think the genetic ones are probably on target. I say that because there is at least one drug that seems to defy the phenomemon of not working a second, third, or fourth time around. That one is Tramadol.
People who respond well to it can stop, go through withdrawals, and restart it with complete effectiveness again. Over and over. They can take drug holidays, return to it, and it works again. If tolerance develops, they can take time off, return to it, and it works again. We all know we can't do that with lexapro, zoloft, or practically anything else. So somehow tramadol is able to work in harmony with genetics. I don't think this holds true 100% of the time, but for most longterm tramadol users they seem to point at that feature as being the thing that makes it stand out from all other antidepressants (though it isn't normally viewed as an antidepressant by clinicians). It happened to be horrible for me, but so many people say it is the best and only real antidepressant on the market.
For sure, none of the drugs I've ever taken work again and none feel at all like they did the first time I took them. I can dream up all the theories I want to, but I know I will never know the answers in my lifetime.
As I usually comment, I think it is important to look outside the box. When neurotransmitter manipulating drugs don't work, then manipulate something else....adrenals, thyroid, blood sugar, pathogen load, food choices, heavy metal load...anything and everything to take a load off the body. Somewhere within that realm lies something that is making the whole depression thing worse than anything else we usually talk about here. My opinion.
Posted by ed_uk2010 on April 24, 2010, at 19:38:37
In reply to Re: Multiple drug exposures and treatment resistence » SLS, posted by bulldog2 on April 24, 2010, at 17:42:59
>The body learns to recognize a foreign substance and how to break it down quickly and get rid of it.
Tolerance due to increased rate of metabolism only occurs with a minority of drugs eg. barbiturate sedatives - which induce the synthesis of drug metabolising enzymes in the liver. Tolerance to the majority of drugs (benzodiazepines, opioids, stimulants etc) is mainly due to cellular adaptations within the central nervous system.
Hope this info is useful.
Posted by Phillipa on April 24, 2010, at 20:25:06
In reply to Re: Multiple drug exposures and treatment resistence » SLS, posted by bulldog2 on April 24, 2010, at 17:42:59
What about if you have an autoimmune disease? The body attacks itself and resistance is down? Phillipa
Posted by ed_uk2010 on April 25, 2010, at 7:48:25
In reply to Re: Multiple drug exposures and treatment resistence » bulldog2, posted by Phillipa on April 24, 2010, at 20:25:06
> What about if you have an autoimmune disease? The body attacks itself and resistance is down? Phillipa
Hi Phillipa,
I don't think Scott has an autoimmune disease. I've not heard him mention any major medical problems apart from bipolar depression.
xx
Posted by Zyprexa on April 25, 2010, at 16:47:44
In reply to Multiple drug exposures and treatment resistence, posted by SLS on April 24, 2010, at 11:53:56
This is why I think that a med trial sould usualy be short.
Posted by linkadge on April 25, 2010, at 19:24:14
In reply to Re: Multiple drug exposures and treatment resistence, posted by Zyprexa on April 25, 2010, at 16:47:44
Perhaps I am missing something but people havn't mentined the obvious question:
Does multiple drug exposures lead to treatment resistance or does treatment resistance lead to multiple drug exposures?
Linkadge
Posted by SLS on April 25, 2010, at 19:39:48
In reply to Re: Chicken or the egg here folks?, posted by linkadge on April 25, 2010, at 19:24:14
Which would you place your bet on?
- Scott
Posted by SLS on April 25, 2010, at 19:59:05
In reply to Re: Chicken or the egg here folks?, posted by linkadge on April 25, 2010, at 19:24:14
> Perhaps I am missing something but people havn't mentined the obvious question:
>
> Does multiple drug exposures lead to treatment resistance or does treatment resistance lead to multiple drug exposures?
I'm betting that both scenarios occur with great frequency.
- Scott
Posted by Phillipa on April 25, 2010, at 20:26:22
In reply to Re: Multiple drug exposures and treatment resistence » Phillipa, posted by ed_uk2010 on April 25, 2010, at 7:48:25
Ed sorry wasn't referring to Scott. I guess I hyjacked sorry about that. Love PJxx
Posted by linkadge on April 25, 2010, at 20:53:31
In reply to Re: Multiple drug exposures and treatment resistence » ed_uk2010, posted by Phillipa on April 25, 2010, at 20:26:22
I dunno.
Which scenario is easier to prove?
The forward direction is easy to see:
Logically, a patient who has inherently treatment resistant depression (to start with) will fail many antidepressant trials.
Proving the converse, that infact multiple antidepressant exposure *produces* treatment resistance requires comprehesive analysis. The study only notes a correlation.
In order to prove this assertion you would need to find a group of patients who:
a) had sucessful initial trials with tidepressants
b) didn't come off this antidepressant because of poop out
c) retried other antidepressants in a similar fashon
d) only later became treatment resistant
Failing any of these, you introduce other possibilities. For instance, if the patient comes off the antidepressant because its not working anymore, then logically they are starting to show signs of resistance even before a subsequent agent is introduced.
Of course it has been a theory that those who keep coming on and off antidepressants fair more poorly, but I would argue the other way around. That people come off the drugs because they're not doing a heck of a lot of good for them.
Linkadge
Posted by linkadge on April 25, 2010, at 20:57:26
In reply to Re: Multiple drug exposures and treatment resistence » ed_uk2010, posted by Phillipa on April 25, 2010, at 20:26:22
Basically you're damned if you do and damned if you don't. Take the drugs, they don't work, come off them...and the doctors have something to blame your treatment resistance on.
In the end, I think it just gives doctors a more positive way to frame things i.e. its patient noncompliance that causes treatment resistance not the fact that the drugs suck.
Linkadge
Posted by SLS on April 25, 2010, at 21:32:51
In reply to Re: Multiple drug exposures and treatment resistence, posted by linkadge on April 25, 2010, at 20:53:31
These are some pretty smart folks. It is probably important to ascertain what is meant by "gradual and stepwise tachyphylaxis" in order to get an idea as to what they were recording and measuring. They were not counting only previous drug failures, but previous successes as well.
- Scott
Posted by SLS on April 25, 2010, at 21:51:02
In reply to Re: Multiple drug exposures and treatment resistence, posted by SLS on April 25, 2010, at 21:32:51
> They were not counting only previous drug failures, but previous successes as well.
I am wrong. They restricted their measurements of previous drug exposure to the current depressive episode.
- Scott
Posted by SLS on April 25, 2010, at 22:13:41
In reply to Re: Multiple drug exposures and treatment resistence, posted by SLS on April 25, 2010, at 21:51:02
"Logistic regression analysis found that an increasing number of prior antidepressant drug exposures was significantly associated with a poorer response to initial sertraline therapy, with a 19.9% lower likelihood of response with each prior antidepressant exposure (odds ratio = 0.81, p = 0.0035)."
The interpretation of these results requires a bit of thought and an understanding of statistics that I sorely lack. The logic here might be counterintuitive.
- Scott
Posted by conundrum on April 26, 2010, at 7:13:21
In reply to Re: Multiple drug exposures and treatment resistence, posted by linkadge on April 25, 2010, at 20:53:31
> a) had sucessful initial trials with tidepressants
>
> b) didn't come off this antidepressant because of poop out
>
> c) retried other antidepressants in a similar fashon
>
> d) only later became treatment resistant
>
Guess thats me, the real reason I stopped prozac was that I didn't bother to get my script refilled and thought maybe I didn't need it anymore. Now I seem to be treatment resistant although I don't know how many drugs you have to fail to be declared treatment resistant.
Posted by SLS on April 26, 2010, at 7:55:05
In reply to Re: Multiple drug exposures and treatment resistence » linkadge, posted by conundrum on April 26, 2010, at 7:13:21
> Guess thats me, the real reason I stopped prozac was that I didn't bother to get my script refilled and thought maybe I didn't need it anymore. Now I seem to be treatment resistant although I don't know how many drugs you have to fail to be declared treatment resistant.
That you have become resistant to the drug that you responded to previously gives evidence that something in the brain has changed since your initial exposure. It may be that physiological adaptations to the drug have occurred as a result of your exposure to it. We know that exposure to these drugs leads to changes in receptor sensitivities. Perhaps such changes in dynamics persist after drug discontinuation. I guess it is also possible that this treatment resistance would have occurred anyway as a result of the natural course of the illness. However, my own experience leads me to believe that drug exposure can indeed produce changes in therapeutic responsitivity. I became unresponsive to Nardil within two weeks of its being discontinued and subsequently restarted. Pulsing of antidepressants is probably a bad idea for some people.
- Scott
Posted by conundrum on April 26, 2010, at 11:16:14
In reply to Re: Multiple drug exposures and treatment resistence » conundrum, posted by SLS on April 26, 2010, at 7:55:05
Great...
Posted by bulldog2 on April 26, 2010, at 12:37:26
In reply to Multiple drug exposures and treatment resistence, posted by SLS on April 24, 2010, at 11:53:56
> Yeah. No kidding...
>
> If you are severely ill, what choice do you have?
>
> I had a doctor tell me that I should remain as clean as possible between trials of newly available medications. He was right. The brain must surely change in response to drug exposure. If it didn't, there would be no such thing as an antidepressant response or the phenomenon of poop-out. Why am I no longer responsive to the same treatment I had success with previously? Something must be different.
>
>
> - Scott
>
>
> -------------------------------------------------
>
>
> Neuropsychobiology. 2009;59(4):227-33. Epub 2009 Jul 2.
>
> Tachyphylaxis after repeated antidepressant drug exposure in patients with recurrent major depressive disorder.
>
> Amsterdam JD, Williams D, Michelson D, Adler LA, Dunner DL, Nierenberg AA, Reimherr FW, Schatzberg AF.
>
> Depression Research Unit, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-3309, USA. jamsterd@mail.med.upenn.edu
> Abstract
>
> OBJECTIVE: The aim of this post hoc analysis was to examine whether tachyphylaxis occurs after repeated courses of antidepressant drug therapy. METHOD: 276 patients with major depressive disorder (MDD) were treated with sertraline (150-200 mg daily) for 8 weeks. Patients with persistent MDD after sertraline therapy were randomized to continuation therapy with either sertraline plus atomoxetine (n = 72) or sertraline plus placebo (n = 74) for 8 additional weeks. Logistic regression was used to test the hypothesis that an increase in prior antidepressant drug exposure is associated with a reduced responsiveness to sertraline therapy. RESULTS: The number of prior antidepressant drug exposures was negatively associated with response to initial sertraline therapy (odds ratio = 0.81, p = 0.0035). The odds ratio indicates a 19.9% reduced likelihood of response with each prior antidepressant treatment trial. In contrast, the number of prior antidepressant treatment trials was not associated with response to continuation sertraline plus atomoxetine or sertraline plus placebo therapy. CONCLUSION: This observation supports the hypothesis that tachyphylaxis may develop after repeated antidepressant drug trials. Copyright 2009 S. Karger AG, Basel.
>
> PMID: 19571597 [PubMed - indexed for MEDLINE]I wonder if you would do the best going back in time to the oldest medication that worked for you. For instance if imipramine was the first ad that worked for you give it another whirl. So work it from oldest to newest if you do retrys. Just a thought.
Posted by conundrum on April 26, 2010, at 14:15:59
In reply to Re: Multiple drug exposures and treatment resistence, posted by bulldog2 on April 26, 2010, at 12:37:26
Hmm, I don't know. I recently found that 2.5 mg prozac gave me some motivation. However it did also give me headaches and diarrhea that I didnt' get the first time. I increased to 5 mg and felt even more blunted. I doubt that going back to the original 20mg.
Also, I don't think the response at 2.5 was adaquate on its own.
Even when it was working I was getting weird pressure headaches in the front of my head, like a sinus headache. My liver functions were also all elevated.
I think overtime the drugs also have greater effects than at their primary receptors and when you go back on the drug that doesn't happen right away. Like prozac has some NRI potency, but I bet after 4 years its a way more potent NRI than after a couple months, especially since the drug inhibits liver enzymes that break it down so it builds up in your blood.
Posted by SLS on April 26, 2010, at 14:46:46
In reply to Re: Multiple drug exposures and treatment resistence » bulldog2, posted by conundrum on April 26, 2010, at 14:15:59
> Hmm, I don't know. I recently found that 2.5 mg prozac gave me some motivation. However it did also give me headaches and diarrhea that I didnt' get the first time. I increased to 5 mg and felt even more blunted. I doubt that going back to the original 20mg.
>
> Also, I don't think the response at 2.5 was adaquate on its own.
>
> Even when it was working I was getting weird pressure headaches in the front of my head, like a sinus headache. My liver functions were also all elevated.
>
> I think overtime the drugs also have greater effects than at their primary receptors and when you go back on the drug that doesn't happen right away. Like prozac has some NRI potency, but I bet after 4 years its a way more potent NRI than after a couple months, especially since the drug inhibits liver enzymes that break it down so it builds up in your blood.
Maybe there is a sensitization process occurring.
- Scott
Posted by Phillipa on April 26, 2010, at 20:28:42
In reply to Re: Multiple drug exposures and treatment resistence, posted by SLS on April 26, 2010, at 14:46:46
Is it really any different from alchohol tolerance, or motrin won't relieve headaches anymore, coffee more and then withdrawal. I feel the aging process changes most if not all of us as homones change. Or bones change, organs age, the heart ages, the brain ages. Phillipa
Posted by conundrum on April 26, 2010, at 20:41:36
In reply to Re: Multiple drug exposures and treatment resistence, posted by Phillipa on April 26, 2010, at 20:28:42
I think most of those tolerances disappear over time. I still can't tolerate SSRIs, its almost more like a negative reaction to them, not just that they don't work.
I also think that having a drug in your body 24hrs a day, everyday, for years produces changes in your body that drugs like motrin, caffeine, and alcohol can't produce since they clear out when you stop using them.
Posted by Bob on April 26, 2010, at 20:44:19
In reply to Re: Multiple drug exposures and treatment resistence » Phillipa, posted by conundrum on April 26, 2010, at 20:41:36
> I think most of those tolerances disappear over time. I still can't tolerate SSRIs, its almost more like a negative reaction to them, not just that they don't work.
>
> I also think that having a drug in your body 24hrs a day, everyday, for years produces changes in your body that drugs like motrin, caffeine, and alcohol can't produce since they clear out when you stop using them.My experience with SSRIs is similar in that I can hardly tolerate them any longer.
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