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Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 11 of 11. This is the beginning of the thread.
Posted by McPac on November 28, 2002, at 2:00:00
HowdyDudy wrote this on another thread above...I'd love your 'take' on this theory AND is there a way to prevent this dopamine depletion?
"The most common theory concerning why ADs poop out revolves around subtle dopamine depletion over the longterm. Many ADs, particularly the newer SSRIs, slowly deplete dopamine over time. As dopamine levels deplete, activation of the antidepressant tends to decrease."
Posted by Larry Hoover on November 28, 2002, at 7:20:39
In reply to Larry Hoover....what are your thoughts on this?, posted by McPac on November 28, 2002, at 2:00:00
> HowdyDudy wrote this on another thread above...I'd love your 'take' on this theory AND is there a way to prevent this dopamine depletion?
>
> "The most common theory concerning why ADs poop out revolves around subtle dopamine depletion over the longterm. Many ADs, particularly the newer SSRIs, slowly deplete dopamine over time. As dopamine levels deplete, activation of the antidepressant tends to decrease."My first reaction is, this is a theory, not an observation. Already that makes me less interested in building more thoughts around it.
Rather than being a depletion of dopamine levels (something I consider to be unlikely), what may instead be happening is the drug is regulated out of its effective range. IMHO, the body has an amazing capacity to change the sensitivity of its receptors, and by multiple mechanisms. As the antidepressant drug is a foreign substance, why wouldn't the body's natural tendency be to deprive it of activity?
Alternatively, the drug may place a burden on particular biochemical pathways which deplete specific nutrients over time. Under this hypothesis, figuring out how to feed the brain appropriately would extend the usefulness of the drug.
I don't much care for theories because they restrict thinking, rather than extending it. I mean that in the sense of adopting a theory as a philosophy of understanding; it becomes dogma, belief in one unprovable thought structure, to the exclusion of others with similar merit.
Posted by BekkaH on November 28, 2002, at 17:38:48
In reply to Larry Hoover....what are your thoughts on this?, posted by McPac on November 28, 2002, at 2:00:00
There is a substantial amount of research which indicates that SSRI-induced dopamine depletion does, in fact, occur. You can start out with Joseph Glenmullen's PROZAC BACKLASH for a number of citations from the medical literature proving that SSRI's can deplete dopamine by up to 50-60%.
Posted by Larry Hoover on November 28, 2002, at 18:11:01
In reply to SSRI-induced dopamine depletion, posted by BekkaH on November 28, 2002, at 17:38:48
> There is a substantial amount of research which indicates that SSRI-induced dopamine depletion does, in fact, occur. You can start out with Joseph Glenmullen's PROZAC BACKLASH for a number of citations from the medical literature proving that SSRI's can deplete dopamine by up to 50-60%.
Dopamine depletion in the prefrontal cortex is associated with remission of depression. You just can't generalize. One of the problems with drugs to control neurotransmitters is that they affect all cells with a certain receptor type the same way, even though you might want some to increase activity and others to be reduced.
Even though dopaminergic activity or total dopamine might fall during antidepressant therapy, there's no way to say whether that's good or not. Nobody knows what it means.
Posted by Larry Hoover on November 28, 2002, at 21:53:06
In reply to SSRI-induced dopamine depletion, posted by BekkaH on November 28, 2002, at 17:38:48
> There is a substantial amount of research which indicates that SSRI-induced dopamine depletion does, in fact, occur. You can start out with Joseph Glenmullen's PROZAC BACKLASH for a number of citations from the medical literature proving that SSRI's can deplete dopamine by up to 50-60%.
I've spent the last few hours researching this issue, and I believe that Glenmullen 'cherry-picked' his data. Even just having access to abstracts of the articles is sufficient to show this. By no means am I trying to trivialize the issue; for those who have EPS arising from SSRIs, it's not the least bit funny.
Here's a summary of what I found. Dopamine suppression does occur, but it is ordinarily transient. It is in direct response to the initial increase in synaptic serotonin caused by uptake receptor blockade. However, both effects subside over a week to ten days. Thereafter, changes in receptor sensitivity are noted, and correspond temporally with reduction in symptoms.
In some small percentage of cases, the decline in overall dopaminergic activity is not followed by upregulation of the dopamine receptors. For those subjects, extra-pyramidal symptoms can arise, e.g. parkinsonism, dyskinesia, akathisia. These symptoms are generally considered to be 'early emergent', i.e. arising within weeks of initiating therapy. Withdrawal of the drug relieves these symptoms.
I don't know if this is what you were referring to, but it is what Glenmullen was talking about.
Here are a couple recent studies which show SSRI responsiveness is correlated to dopamine receptor upregulation.
J Psychopharmacol 2000 Jun;14(2):152-6
Comment in:
J Psychopharmacol. 2000;14(4):419.Dopaminergic sensitivity and prediction of antidepressant response.
Healy E, McKeon P.
Department of Psychological Medicine, Institute of Psychiatry, London, UK. [email protected]
This study was designed to examine neuroendocrine predictors of antidepressant response to the selective serotonin reuptake inhibitor (SSRI) paroxetine. We assessed the prognostic utility of the apomorphine stimulation test by examining the relationship between pretreatment change in growth hormone (GH) following apomorphine and acute response to paroxetine treatment. We hypothesized that those subjects with most marked pretreatment dopaminergic supersensitivity, as manifested by greatest change in GH, would be most likely to show an early antidepressant response and would also be more likely to develop manic or hypomanic symptoms on paroxetine. Contrary to our hypothesis, greater dopamine postsynaptic sensitivity was associated with greater resistance to paroxetine treatment. In our sample of 13 subjects with a major depressive episode, pretreatment GH response to apomorphine per unit weight was inversely correlated with change in Hamilton depression rating scale following 6 weeks of paroxetine. Within the group of subjects who showed mood elevation on paroxetine, there was a trend towards greater GH response being associated with slower antidepressant response. With regard to the development of manic or hypomanic symptoms on paroxetine, change in GH per unit weight not did distinguish the two subjects who subsequently developed paroxetine-induced hypomania from other subjects. The seven subjects with previous antidepressant-induced hypomania did not differ from the other subjects in change in GH response per unit weight. The finding that subjects who had low dopamine receptor responsivity pretreatment were more likely to have an antidepressant response with paroxetine is consistent with recent suggestions that the therapeutic effect of SSRIs may be mediated through increased dopamine receptor sensitivity in the mesolimbic system. Further work assessing pretreatment and post-treatment GH response to apomorphine will help to test the hypothesis that low dopamine receptor responsivity predicts antidepressant response to SSRIs.
Psychiatry Res 1999 Apr 26;90(2):91-101
Dopamine D2 receptor binding before and after treatment of major depression measured by [123I]IBZM SPECT.
Klimke A, Larisch R, Janz A, Vosberg H, Muller-Gartner HW, Gaebel W.
Department of Psychiatry, University of Dusseldorf, Germany. [email protected]
Fifteen patients fulfilling DSM-IV criteria for major depression were investigated with the specific dopamine D2 receptor antagonist [123I]iodobenzamide (IBZM). Two single photon emission computed tomography (SPECT) examinations were performed before and after 6 weeks of treatment with a selective serotonin re-uptake inhibitor (SSRI). Striatal D2 receptor binding was calculated and normalized to the cerebellum. In a non-psychiatric control group (n = 17), which was investigated once with [123I]IBZM and SPECT, striatal IBZM binding decreased significantly with age (0.092 per decade). The age-dependent correlation was lower in subjects with major depression and did not reach statistical significance. There was no significant difference in mean IBZM binding between depressives and control subjects. Age-corrected baseline IBZM binding in the striatum was significantly lower in treatment responders than in depressed non-responders and control subjects. Furthermore, in the depressive group there was a significant linear correlation between treatment response and change of D2 receptor binding during treatment in the basal ganglia. IBZM binding increased in treatment responders and decreased in non-responders. In accordance with animal studies, the results suggest an association between changes in the dopaminergic system and treatment response in major depression.
Posted by oracle on November 29, 2002, at 0:05:56
In reply to Re: SSRI-induced dopamine depletion, posted by Larry Hoover on November 28, 2002, at 18:11:01
> Dopamine depletion in the prefrontal cortex is associated with remission of depression. You just can't generalize. One of the problems with drugs to control neurotransmitters is that they affect all cells with a certain receptor type the same way, even though you might want some to increase activity and others to be reduced.
>
> Even though dopaminergic activity or total dopamine might fall during antidepressant therapy, there's no way to say whether that's good or not. Nobody knows what it means.
I put it another way, once you start talking about depletion in the context of causing mental illness you are way off, and have missed the complexity of these systems and are ignoring how much we do not know.Or to put it another way, if it was depletion that caused mental illness, they would of been cured decades ago.
Posted by BrittPark on November 30, 2002, at 18:54:28
In reply to Re: SSRI-induced dopamine depletion, posted by Larry Hoover on November 28, 2002, at 18:11:01
I find the dopaminergic system to be puzzling. Excess dopamine is associated with psychosis. It seems also to be the mechanism by which speed and related drugs induce pleasure. In general the dopamine system is at least partially associated with the ability to experience reward.
This is highly speculative, but could SSRI dopamine depletion be responsible for the flattened affect that many people report?
I'd be interested in your thoughts.
Cheers,
Britt
Posted by Kari on December 1, 2002, at 12:06:43
In reply to Re: SSRI-induced dopamine depletion » Larry Hoover, posted by BrittPark on November 30, 2002, at 18:54:28
This may be a dumb question, but if SSRIs cause a generalized dopamine depletion in the brain rather than binding to specific recepters, wouldn't one expect them to have an antipsychotic effect?
Posted by Larry Hoover on December 1, 2002, at 12:09:29
In reply to Re: SSRI-induced dopamine depletion » Larry Hoover, posted by BrittPark on November 30, 2002, at 18:54:28
> This is highly speculative, but could SSRI dopamine depletion be responsible for the flattened affect that many people report?
>
> I'd be interested in your thoughts.
>
> Cheers,
>
> BrittCould it? Yes, but I'm answering as a scientist. It has a non-zero probability, so it could.
My opinion? I think people are far too attached to explanations. The facts are that antidepressant effects can diminish over time. Thinking we might know why has no bearing on whether or not antidepressant effects diminish.
If having an explanation makes you feel better, so be it. I don't have an explanation, and I seriously doubt that dopamine depletion is the explanation. If that was the case, taking l-dopa would fix the problem, but it doesn't.
Posted by BrittPark on December 1, 2002, at 12:40:46
In reply to Re: SSRI-induced dopamine depletion, posted by Larry Hoover on December 1, 2002, at 12:09:29
> Could it? Yes, but I'm answering as a scientist. It has a non-zero probability, so it could.
>
> My opinion? I think people are far too attached to explanations. The facts are that antidepressant effects can diminish over time. Thinking we might know why has no bearing on whether or not antidepressant effects diminish.As a scientist myself, I think explanations are always desirable. Of course we are (relatively) in the dark about the mechanism of psychopharmaceuticals. It's important that we don't stay that way.
>
> If having an explanation makes you feel better, so be it. I don't have an explanation, and I seriously doubt that dopamine depletion is the explanation. If that was the case, taking l-dopa would fix the problem, but it doesn't.
>Has somebody done a study showing this?
CordiallyBritt
Posted by Larry Hoover on December 1, 2002, at 14:04:10
In reply to Re: SSRI-induced dopamine depletion » Larry Hoover, posted by BrittPark on December 1, 2002, at 12:40:46
> > Could it? Yes, but I'm answering as a scientist. It has a non-zero probability, so it could.
> >
> > My opinion? I think people are far too attached to explanations. The facts are that antidepressant effects can diminish over time. Thinking we might know why has no bearing on whether or not antidepressant effects diminish.
>
> As a scientist myself, I think explanations are always desirable. Of course we are (relatively) in the dark about the mechanism of psychopharmaceuticals. It's important that we don't stay that way.
> >
> > If having an explanation makes you feel better, so be it. I don't have an explanation, and I seriously doubt that dopamine depletion is the explanation. If that was the case, taking l-dopa would fix the problem, but it doesn't.
> >
>
> Has somebody done a study showing this?
>
>
> Cordially
>
> BrittI've seen anecdote, but I can't find an example right now. As an aside, there seems to be a great deal of confusion between dopamine down-regulation and dopamine depletion. They are not equivalent processes.
Back to the original question, I'm not questioning the utility of mechanistic thinking....certainly that is of prime importance in experimental design and hypothesis-testing. However, I'm becoming more and more an empiricist as time goes on. Observations are the only facts we have. All the rest is speculation.
In the context of the dopamine-depletion hypothesis, it seems to be much like the serotonin-deficiency hypothesis of depression. If it was as simple as that, SSRIs would not have delayed onset.
This is the end of the thread.
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