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Re: SSRI-induced dopamine depletion

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.

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.

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.




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