Venlafaxine (Effexor) is an extremely weak antidepressant...

[Biochemistry]

Contrary to popular perception, venlafaxine (Effexor) is, in fact, an extremely weak antidepressant. If you take a look at the following document: http://consortiumconcepts.com/Library_files/Antidepressant%20Pharmacology%202001.pdf, you will see that venlafaxine should not even be classified as an SNRI. At best, it should be classified as a very weak SSRI. Citalopram is a weak SSRI, but it is nine times more potent than venlafaxine on the serotonin transporter. Paroxetine (Paxil) is by far the most potent SSRI, and is MUCH more of an SNRI than venlafaxine. Its affinity for the norepinephrine transporter is 25 fold more potent than venlafaxine. Also, paroxetine's affinity for the serotonin transporter is 80 fold more potent than venlafaxine.

Is there anybody out there who has been on venlafaxine and found it to be weak in comparison with other SSRIs, for example?

 

[AlphaMethylPhenyl]

As I understand it Venlafaxine works largely because of downstream activity at the mu and delta opiate receptor.

 

[Epsilon Alpha]

Affinity=/= efficacy as an antidepressant. Last I checked paroxitine was one of the least effective on the market despite its high SERT affinity.

 

[mysticgreen]

as far as I understand, the effects of SSRIs are not quite understood yet, and there must be other mechanisms than just SERT inhibition to explain antidepressant effects. therefore, affinity for SERT may not be the only parameter to discuss here.

could maybe anyone with more knowlegde recommend some introductionary or review papers on this issue?

 

[Biochemistry]

Affinity=/= efficacy as an antidepressant. Last I checked paroxitine was one of the least effective on the market despite its high SERT affinity.

There is clearly a correlation between efficacy and neurotransmitter affinity. Although I now dislike paroxetine, when I was first prescribed it, it was definitely the most effective option for my rather severe case of OCD and depression (I had tried fluoxetine and amitriptyline prior to this). I also think it depends on the condition that you're endeavouring to treat. There is a fair amount of scientific evidence that suggests there is a major serotonin dysfunction in OCD, and it is no surprise that the medications with the highest binding affinity for serotonin are considered to be the most effective, i.e: paroxetine, sertraline and clomipramine. Also, I think it depends entirely on the severity of the illness, for example, major depression with melancholic features. Melancholic depression, for example, will respond extremely well to the more powerful antidepressants, such as paroxetine, sertraline or clomipramine. Same for severe OCD. For milder cases of mental illness, I believe that milder medications are much more suitable, such as citalopram.

I am still confused about venlafaxine, though. It appears to be extremely weak on SERT and NA (even sertraline has a higher affinity for NA than venlafaxine), yet highly efficacious for severe depression. I am not convinced that this is due to opioid involvement due its extremely weak affinity for these receptors. I would also be interested if anybody could enlighten me on this.

 

[AlphaMethylPhenyl]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171132/

 

[Epsilon Alpha]

There is clearly a correlation between efficacy and neurotransmitter affinity.

I am still confused about venlafaxine, though. It appears to be extremely weak on SERT and NA (even sertraline has a higher affinity for NA than venlafaxine), yet highly efficacious for severe depression. I am not convinced that this is due to opioid involvement due its extremely weak affinity for these receptors. I would also be interested if anybody could enlighten me on this.

Affinity has a minimal effect on efficacy, its mostly how specific drugs trigger downstream transcriptional changes and changes in various cellular processes that exerts the antidepressant effect. But, with that said all antidepressants have a similar level of efficacy. However, one can argue that side effects and specific binding profiles can make a particular drug the best in a specific situation.
http://www.sciencedirect.com/science/article/pii/S0140673609600465

IIRC venlafaxine is dosed quite high relative to other antidepressants. That could easily get around some of the lower affinity issues, or who knows maybe is a potent agonist at a novel target that has not yet been identified.