Time lag of AD's - receptor desensitization - legit?

[JohnBoy2000]

Is this a plausible theory?

I ask because, I'm curious as to how long I should wait to consider the full therapeutic effect of a drug to have taken place.

One argument seems to be the downstream modification of gene expression, and protein synthesis?
A very synopsized means of referring to things I don't fully (barely partly) understand, as a means to allude to the possible explanation for AD's time lag.

The other theory being, receptor hypersensitivity being a cause of depression, in addition to low NT levels - though drugs depleting NT levels don't induce depression in normal folk - so perhaps that theory is more relevant regarding the receptor sensitivity part?

But how long would it take receptors to desensitize.
Past 4 weeks or more?

And has there been additional research information as to whether this is a plausible explanation for the therapeutic effects of AD's??

 

[aced126]

Well ADs of the SSRI class start to work over a timescale of weeks, and they are believed to work via downstream effects of serotonin release, like autoreceptor synthesis. So yeah, maybe it takes a couple of weeks for receptors involved in SSRI action to desensitize?

 

[Cotcha Yankinov]

There are some benefits to the downregulation of autoreceptors that occurs with chronic SSRI administration but that's certainly not the whole picture. Part of the picture is that after downregulation of homeostatic mechanisms, 5-HT signaling can increase significantly and then the genetic changes that occur with SSRI administration can start to take place. One benefit to an increase in 5-HT signaling would reversal of stress induced deficits in neurotrophic signaling cascades. Essentially neurotrophic compounds like BDNF might not be quite as useful if there is hypo-expression of receptors for it to bind to (TrkB).

I think there is some agreement from what I've read in the literature that SSRIs can take up to a year to work.

Note that this applies specifically to SSRIs. I'm still not convinced of the long term efficacy of NRIs even if they help with some symptoms in the short term.

The other thing is that a (controversial) meta-analysis suggests that SSRIs are only really better than placebo in severe depression - moderate and mild depression is a different story. So what exactly you have got going on is relevant. There are different depression phenotypes.

 

[d1nach]

It is my understanding that selective seritonin reuptake inhibitors cause significant reduction in depressive symptoms after 8 to 12 weeks of daily consumption given sufficient dosage where the depression is severe, a large portion of the severely depressed experience no benefit and a large portion only show a partial reduction.

With that being said please keep in mind many alternative supplements may appear much more effective but ssris are extremely studied and their slight benefit is actually quite large given most things fail to do anything at such level of scruitiny

 

[Cotcha Yankinov]

Yes, I think some benefits and a reduction of therapy initiation related side effects are expected around 12 weeks.

Single administration of an SSRI to animals results in a reduction of serotonergic neuron firing in the cortex, this is facilitated by autoreceptors but this response is desensitized with time.

There are some studies showing some immediate benefit to autoreceptor antagonist (pindolol) augmentation of SSRI therapy, although I don't think that's a good long term idea.

 

[serotonin2A]

Yes, I think some benefits and a reduction of therapy initiation related side effects are expected around 12 weeks.

Single administration of an SSRI to animals results in a reduction of serotonergic neuron firing in the cortex, this is facilitated by autoreceptors but this response is desensitized with time.

There are some studies showing some immediate benefit to autoreceptor antagonist (pindolol) augmentation of SSRI therapy, although I don't think that's a good long term idea.

Benefits of SSRIs can occur in as little as 2 weeks, but it usually takes 4-6 weeks for SSRIs to be fully effective (longer for fluoxetine due to its long half-life).

Pindol was tested as a potential way to augment SSRIs, but it didn't reduce the delay between treatment onset and symptom improvement. I would imagine the problem is that the structural/functional changes underlying antidepressant response proceed rather slowly; speeding up the initial step of 5-HT autoreceptor desensitization apparently doesn't speed up the downstream changes that mediate the antidepressant response.

 

[Cotcha Yankinov]

Hey Sero, I haven't actually read any of the following studies so I may have read too much into their titles but just thought I would post this
(From https://www.ncbi.nlm.nih.gov/pubmed/19428959/)

"5-HT_1A autoreceptor antagonist pindolol has been reported to accelerate SSRI-driven AD response by blocking the initial negative feedback mediated by increased raphe 5-HT_1A autoreceptor binding (Artigas et al 1994) (Zanardi et al 1997) (Zanardi et al 1998) (Hjorth et al 2000) (Zanardi et al 2001) (Berney et al 2008). Nevertheless, a number of clinical trials have questioned the clinical utility of both buspirone and pindolol (Berman et al 1997) (Berman et al 1999) (Perry et al 2004)"

I do notice there are some conflicting studies reported at the end there, and I also remember a study that seemed to suggest that pindolol offered only a temporary (and modest) improvement as an adjunct to SSRIs.

Anyhow, you are spot on about some people seeing improvement at around 2 weeks but I'm curious how long you think SSRIs should be given a chance to work? I understand it also may not be a matter of completely abandoning the SSRI at that point, but rather choosing an adjunct. Is something like 3 months an okay time to start re-thinking the efficacy of the SSRI by itself?

As an aside I will throw it out there that an MDMA/ecstasy adverse effects sufferer saw immediate benefits to his use of Sertraline, certainly a unique case there though.

 

[serotonin2A]

Hey Sero, I haven't actually read any of the following studies so I may have read too much into their titles but just thought I would post this
(From https://www.ncbi.nlm.nih.gov/pubmed/19428959/)

"5-HT_1A autoreceptor antagonist pindolol has been reported to accelerate SSRI-driven AD response by blocking the initial negative feedback mediated by increased raphe 5-HT_1A autoreceptor binding (Artigas et al 1994) (Zanardi et al 1997) (Zanardi et al 1998) (Hjorth et al 2000) (Zanardi et al 2001) (Berney et al 2008). Nevertheless, a number of clinical trials have questioned the clinical utility of both buspirone and pindolol (Berman et al 1997) (Berman et al 1999) (Perry et al 2004)"

I do notice there are some conflicting studies reported at the end there, and I also remember a study that seemed to suggest that pindolol offered only a temporary (and modest) improvement as an adjunct to SSRIs.

Anyhow, you are spot on about some people seeing improvement at around 2 weeks but I'm curious how long you think SSRIs should be given a chance to work? I understand it also may not be a matter of completely abandoning the SSRI at that point, but rather choosing an adjunct. Is something like 3 months an okay time to start re-thinking the efficacy of the SSRI by itself?

As an aside I will throw it out there that an MDMA/ecstasy adverse effects sufferer saw immediate benefits to his use of Sertraline, certainly a unique case there though.

The results have been conflicting. It seems like patients with treatment resistant or recurrent depression don't receive any benefit from pindolol, whereas more acute cases show some response.

8 weeks is probably a good point to evaluate whether to try another medication or an adjunct treatment.