Based upon the monoamine hypothesis of depression (i.e. you’re messed up due to an imbalance of one or more of three of the best understood neurotransmitters: serotonin, norepinephrine, and/or dopamine), Effexor attempts to balance your brain juices by inhibiting the reuptake (in English: delaying the breaking down and recycling) of serotonin and norepinephrine at their receptors in various (i.e. depending on which studies and books you’ve read and fancy brain scans you’ve looked at) locations in your brain. It may do a lot of other things that address depression, anxiety, other brain cooties and some off-label uses by encouraging the growth of new neurons, affecting hormones and CYP450 genes in your brain, and who knows what else. You also have serotonin and norepinephrine receptors throughout your body, especially in your GI and renal systems, which is why SSRIs & SNRIs are used to treat various conditions like IBS and incontinence. As it doesn’t really affect norepinephrine until you reach a dosage of at least 225mg a day (or 175–200 for IR), it is practically an SSRI, and thus not as effective for pain and pain-related conditions like fibromyalgia as other SNRIs like Cymbalta and Pristiq.
The active metabolite o-desmethylvenlafaxine (ODV) does most of the work, and is now available in a refined form as Pristiq ( desvenlafaxine ).
When you compare venlafaxine with other SSRIs and SNRIs you’ll find, in terms of raw potency, it’s the weakest reuptake inhibitor of any med defined as a serotonin- or norepinephrine-reuptake inhibitor. So why is it so effective? And, presumably, why are its discontinuation symptoms so awful? The answer has to be found in its pharmacokinetics (PK).
The half-life of venlafaxine HCl is 3–7 hours , and ODV’s half-life is 9–13 hours . That means it takes two days for one and five days for the other to clear out of your system. Having two parts with short half-lives is a huge part of why the discontinuation syndrome is so freaking harsh.
The other PK stats for venlafaxine XR and ODV are:
- PK is linear
- Cmax 150 ng/mL for venlafaxine and 260 ng/mL for ODV
- Tmax is 5.5 hours for venlafaxine and 9 hours for ODV
- Apparent volume of distribution is 7.5±3.7 L/kg for venlafaxine and 5.7±1.8 L/kg for ODV
- Steady-state plasma clearance is 1.3±0.6 L/h/kg for venlafaxine and 0.4±0.2 L/h/kg for ODV
- Absolute bioavailability for venlafaxine is 45%
- Plasma protein binding is 27% for venlafaxine and 30% for ODV
- 92% of a single oral dose of venlafaxine is absorbed.
That last parameter is something I rarely see anywhere. When I do see it, it’s never close to 50%. While venlafaxine’s absolute bioavailability is low, the low plasma protein binding, spectacular, as far as I can tell, absorption, and truly spectacular Cmax (Twice as high as the similarly weak bupropion and 4–5 times greater than all the other antidepressants where I have that number) explains why a drug with such a piss-poor effect on the neurotransmitter transporters is so freaking effective. Basically what it lacks in strength it makes up for by getting more of the active ingredient where it needs to be.
So if this site ever starts making money again I’ll have to get the numbers for a lot of other meds and do the math to update the equivalencies.
venlafaxine hydrochloride and the active metabolite o-desmethylvenlafaxine