PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs. Antidepressants - Venlafaxine.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Antidepressants - Venlafaxine

Antidepressants - Venlafaxine

Date Created: 02/09/1999   Last Modified: 11/09/2003   Last Checked: 14/03/2003   

Venlafaxine is one example of a drug whose 'tag' (that it is an 'SNRI') may relate to marketing imperatives as much as it does to pharmacology.

It is dubbed a serotonin and noradrenalin reuptake inhibitor (SNRI) but it may only have a clinically significant effect on noradrenalin in vivo at higher doses, if at all.

Venlafaxine is extremely weak as a noradrenalin reuptake inhibitor. It is one thousand times weaker than desipramine as a noradrenalin reuptake inhibitor in 'test tube' assays (ie 'in vitro') and more than 100 times less potent than amitriptyline or nortriptyline. This indicates that it may not be justified to classify it as an serotonin and noradrenalin reuptake inhibitor (‘SNRI’) and that additional evidence that it has such actions in humans is required before the proposition of dual action can be accepted with any confidence

Two findings go against the dual action notion: it has a lesser effect in reducing the hypertensive response to tyramine than known noradrenalin reuptake inhibitors (NRIs). Also incubation of human fibroblasts with desipramine or reboxetine, but not with venlafaxine, caused a highly significant reduction in nuclear CREB-P; which suggests desipramine and reboxetine (noradrenergic antidepressants), but not venlafaxine, exert direct noradrenergic effects beyond beta adrenoceptors (Sulser, F. 2002).

All this indicates venlafaxine is not a clinically significant noradrenalin reuptake inhibitor (NRI) in usual doses in humans.

Indeed, in vitro venlafaxine is a weaker noradrenalin reuptake inhibitor than is fluoxetine (and some other 'SSRIs'). Fluoxetine is of course marketed as an selective serotonin reuptake inhibitor.

In summary we have the anachronism that some drugs marketed as selective serotonin reuptake inhibitors (SSRIs) are more potent noradrenalin reuptake inhibitors than venlafaxine, which is marketed as a serotonin and noradrenalin reuptake inhibitor (SNRI). This is only partly explained away by 'selectivity' (ie the ratio of NA vs 5-HT potency) and different dose ranges.


Noradrenalin reuptake inhibitor potency ***
Desipramine 0.83 most potent
Amitriptyline 35
Fluoxetine 240
Venlafaxine 1060 weakest

*** After Richelson; for explanation and details see note about 'receptor affinities'

Venlafaxine may be best thought of as an odd serotonin reuptake inhibitor.

In Aug 2003 Wyeth announced the findings of lack of effect in all non-adult patients against both depression and generalised anxiety disorder and also the important and problematic finding of increased suicidal behaviour as well as increased hostility (in those on venlafaxine compared to those on placebo). Many people might wonder how much younger patients can really differ from adults. In that light such results create even more confusion about what these drugs (serotonin reuptake inhibitors) are really doing. The evidence that their effects are greatly oversold and greatly over-estimated continues to mount, and is now considerable: in my opinion it is convincing. Even more importantly, it fits with clinical experience (ie that venlafaxine does not work very well).

See especially BJP 2003 Parker et al for a balanced discussion of the general notion that antidepressant drug trials are confusing, invalid, unhelpful to clinicians and largely a waste of paper.

Although much has been written about venlafaxine's superior effectiveness, and also its supposed rapid onset of action in severe depression, the evidence to support that notion remains modest. Recent meta-analysis findings (Andersen, I. 2002 May BJP) indicate venlafaxine is not superior in efficacy to amitriptyline, but may possibly be superior to SSRIs. Any superiority over SSRIs is marginal and is likely to be of no clinical relevance. Note that Andersen has also shown study sponsorship is a stronger factor increasing treatment effect size than any difference between different drugs, or drugs and placebo.

Current evidence clearly demonstrates venlafaxine has greater toxicity in over-dose (and more severe withdrawal effects) than any other new antidepressant (including all SSRIs, nefazodone, mirtazapine, reboxetine, moclobemide) as well as some of the 'old' tricyclic antidepressants (TCAs).

The slow release formulation may cause increased problems and toxicity following over-dose, even after activated charcoal and whole-bowel irrigation.

Recent data (12/00) from 456 admissions with antidepressant poisoning; numbers:--
venlafaxine (51), tricyclic antidepressants (excluding dothiepin*) (172), SSRI (233), dothiepin (81).
* because it is so much more toxic than all the others

Odds ratios (95% CIs, p) for:--

Seizures
Venlafaxine vs TCAs-- 4.4 (1.2 – 16.6, p = 0.02)

Prolonged QRS (to >= 100 ms)
SSRIs vs TCAs 0.3, (0.2 – 0.6, p < 0.0001)
TCAs vs venlafaxine 0.6 (0.3 – 1.4, p = 0.31)

Serotonin syndrome
venlafaxine vs TCAs 35.4 (7.6 – 325.3, p < 0.0001)
SSRIs vs TCAs 20.4 (5.2 – 174.9, p < 0.0001)

Conclusions: Venlafaxine in overdose is pro-convulsant (and cardiotoxic), even more than TCAs (whereas SSRIs are much less so). Venlafaxine is also more likely to cause serotonin toxicity (serotonin syndrome) than either TCAs or SSRIs; this is unexpected since it is generally a weaker SRI. This would fit with it having another mechanism of action as mooted above.

The above figures on toxicity from Whyte are similar to Buckley et al (BMJ dec 2002) from their analysis of the UK database.

The (sometimes) severe withdrawal effects seem to be characterised by:--
headache, nausea, fatigue, dizziness and dysphoria. In some cases even slow tapering has not helped; it is not likely that the slow release preparation will make much difference to withdrawal effects. As with serotonin reuptake inhibitors it is probable that dose and duration of treatment will be relevant factors, ie high doses and longer time on treatment leads to greater likelihood of withdrawal symptoms.

It is concerning that venlafaxine has a close structural similarity to tramadol (a new narcotic analgesic). There is a suggestion that venlafaxine has analgesic effects that are blocked by naloxone; so could it be acting partly as an opioid drug? However, latest data suggests it may not bind to any opiate receptor sub-types.

Indications are that venlafaxine, and tramadol, are particularly prone to interact with MAOIs and thus be implicated in severe and fatal serotonin toxicity (serotonin syndrome). More so, it seems, than the other SSRIs: that suggests an extra different mechanism of action.

Venlafaxine, when used in larger doses of over ~150 mg, may cause an increase in blood pressure in some people, another aspect that requires monitoring, and may be a problem in some patients.

What the place of venlafaxine should be at lower doses (ie up to ~150 mg) in primary care is hard to judge. It shares the low interaction propensity (via cytochrome P450 enzymes) of sertraline and citalopram; but at lower doses probably has no particular advantages and is more toxic in over-dose than any of the SSRIs, or even than some of the old tricyclic antidepressants. Remember its supposed superiority over selective serotonin reuptake inhibitors (SSRIs) only applies to higher dose levels, over ~ 300 mg per day and is doubtful.

It behoves us all to be especially cautious about drugs when there is uncertainty over the mechanism of their action. Venlafaxine's toxicity in over-dose and its similarities to the narcotic analgesic 'tramadol' warrant monitoring and caution; although some data suggests it does not have significant affinity at opiate receptors (Bymaster 2001).

My evaluation of the current evidence is that venlafaxine should be used sparingly in primary care settings with care and due recognition of the uncertainties surrounding it; whether it will prove suitable, or acceptably safe, as a treatment for generalised anxiety disorder will, I think, certainly become a contentious issue. Wyeth, who make venlafaxine, may be wise to re-evaluate the position. Doctors would be prudent if they kept themselves closely informed about the risk benefit ratio with this drug. I my opinion it is significantly less suitable for the indications of depression or generalised anxiety disorder than alternatives.

History repeatedly demonstrates that new is not usually better. History is repeatedly ignored.

The FDA have recommended an amendment of the product information on venlafaxine (2000) as follows:--

"Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine.... Abrupt discontinuation or dose reduction... is associated with the appearance of new symptoms, the frequency of which is increased at higher doses and with longer duration of treatment.

Reported symptoms:--

agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.

It is therefore recommended that the dosage of Effexor be tapered gradually and the patient monitored. The period required for tapering may depend on the dose, duration of therapy and the individual patient."

I do not usually provide many references. There are various reasons for this. Where names of particular researchers are given anyone can look them up for themselves in seconds via Pub Med, google, or 'Endnote, Ref Manager' etc. In doing that you will learn a little about how to find information and also you will find references that have been published since the text was written. If you do not have the ability, the time, the energy, or the knowledge to do that, then you are best off judging the value of my writing and opinion by your general impressions. If there is a reference you are aching to find and read then email me.

Refs

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