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1999, Benmansour Effects of Chronic Antidepressant Treatments on Serotonin Transporter Function, Density, and mRNA Level

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Altostrata

This is one of the early studies discussing downregulation and possible causes of tachphylaxis (poop-out) to SSRIs.

 

It does not address recovery from downregulation.

 

J Neurosci. 1999 Dec 1;19(23):10494-501.

Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level.

Benmansour S1, Cecchi M, Morilak DA, Gerhardt GA, Javors MA, Gould GG, Frazer A.

 

Abstract at https://www.ncbi.nlm.nih.gov/pubmed/10575045 Free full text at http://www.jneurosci.org/content/19/23/10494.long

 

To investigate functional changes in the brain serotonin transporter (SERT) after chronic antidepressant treatment, several techniques were used to assess SERT activity, density, or its mRNA content. Rats were treated by osmotic minipump for 21 d with the selective serotonin reuptake inhibitors (SSRIs) paroxetine or sertraline, the selective norepinephrine reuptake inhibitor desipramine (DMI), or the monoamine oxidase inhibitor phenelzine. High-speed in vivo electrochemical recordings were used to assess the ability of the SSRI fluvoxamine to modulate the clearance of locally applied serotonin in the CA3 region of hippocampus in drug- or vehicle-treated rats. Fluvoxamine decreased the clearance of serotonin in rats treated with vehicle, DMI, or phenelzine but had no effect on the clearance of serotonin in SSRI-treated rats. SERT density in the CA3 region of the hippocampus of the same rats, assessed by quantitative autoradiography with tritiated cyanoimipramine ([(3)H]CN-IMI), was decreased by 80-90% in SSRI-treated rats but not in those treated with phenelzine or DMI. The serotonin content of the hippocampus was unaffected by paroxetine or sertraline treatment, ruling out neurotoxicity as a possible explanation for the SSRI-induced decrease in SERT binding and alteration in 5-HT clearance. Levels of mRNA for the SERT in the raphe nucleus were also unaltered by chronic paroxetine treatment. Based on these results, it appears that the SERT is downregulated by chronic administration of SSRIs but not other types of antidepressants; furthermore, the downregulation is not caused by decreases in SERT gene expression.

 

 

From the paper:

 

There is at least one interesting potential clinical implication of these data. There seems to be some proportion of depressed patients who respond beneficially to SSRI treatment but in whom the benefit wanes over time (Byrne and Rothschild, 1998). One wonders if this may be attributable to a drug-induced loss of the SERT, such that the initial cellular target responsible for the beneficial effect of SSRIs is markedly diminished. This phenomenon has not been well-studied with controlled trials (Byrne and Rothschild, 1998). Somewhat more extensively studied, but again not with controlled trials, has been subsequent response of SSRI-nonresponders (Thase and Rush, 1997; Thase et al., 1997). It does appear that either raising the dose of the SSRI or switching to a different SSRI is successful, in perhaps 40–70% of the patients. Although quite speculative, perhaps SSRI-induced loss of the SERT provides part of the explanation of why some patients do not respond to such strategies.

 

In conclusion, the therapeutic efficacy of SSRI and non-SSRI antidepressants probably derives from different adaptive changes. The SSRIs (paroxetine and sertraline) decrease SERT density and reduce SERT function, as indicated by failure of fluvoxamine to prolong 5-HT clearance. Whether this is produced by all SSRIs remains to be established. Nevertheless, non-SSRI antidepressants gave no evidence of altering SERT function and did not decrease SERT density.

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