Venlafaxine structure

Drugs of the Month:
Venlafaxine (Effexor) and
Desvenlafaxine (Pristiq)

Don’t prescribe it for someone with heart disease

Biological mechanism

Venlafaxine has been marketed as a serotonin-norepinephrine reuptake inhibitor (SNRI), as a way to try to differentiate it from other serotonin repute inhibitors (SRIs).  But in fact, venlafaxine is just another potent SRI, with some noradrenergic reuptake blockade at higher doses.    It isn’t the reverse:  it isn’t a potent noradrenergic reuptake blocker, with some serotonin reuptake blockade.  In this sense, it is much more like fluoxetine (Prozac) than it is like  duloxetine (Cymbalta).  Fluoxetine is the classic SRI prototype, but many clinicians don’t realize that it also has some norepinephrine reuptake blockade, similar in potency in fact, in animal studies, to venlafaxine.  In contrast, duloxetine is a much more potent norepinephrine reuptake blocker than venlafaxine, while still having some serotonin reuptake blockade (unlike the purely potent norepinephrine reuptake blocker, desipramine).  

In other words, venlafaxine is much more like other SRIs than being like classic noradrenergic agents like desipramine.

Clinical efficacy

Like other SRIs venlafaxine has proven efficacy in MDD, mostly in moderate to severe cases, not mild MDD.  There are some data of more benefit with venlafaxine in hospitalized depression compared to other SRIs.  However, specific randomized studies of venlafaxine in patients who failed SRIs found that venlafaxine is NOT more effective than other SRIs in that setting of treatment-resistant depression (unlike the adjunctive efficacy proven with aripiprazole and brexpiprazole). 

It has few drug interactions and can be used without much concern about liver interactions, unlike some other SRIs. 

Fast facts: Venlafaxine (Effexor®) 

Typical dose:  150-300 mg/d (range 75-375 mg/d)

Biological mechanism: serotonin and norepinephrine reuptake inhibition

Typical side effects: sexual dysfunction, sedation

Medically important side effects:  sudden cardiac death, hypertension

Clinically proven efficacy: FDA indications for MDD,  panic disorder


At low doses (37.5-75 mg/d) venlafaxine is more purely serotonergic and has anxiolytic effects. Its mean effective dose in the MDD studies was about 225 mg/d (with a range of 150-300 mg/d).  Though it can be dosed higher, it hasn’t been proven to be more effective for MDD above 300 mg/d than below that dose. 

Cardiac Harms

Most US clinicians don’t realize that venlafaxine is one of the most dangerous antidepressants to use in the setting of cardiovascular disease (in contrast to other agents, like sertraline, proven relatively safe in that setting). There were some cases of sudden cardiac death with venlafaxine, which were not known until some years after its introduction to the marketplace in the 1990s. Awareness of these cases led the UK regulatory body to contraindicate it in 2004 in all persons with hypertension or heart disease. After some protest from clinicians and the relevant pharmaceutical company, the UK regulatory body revised its restriction in 2006 to restrict venlafaxine use only in persons with uncontrolled hypertension or in persons at high risk of ventricular arrhythmia. 

It’s well known that venlafaxine raises blood pressure. The amount of increase has been downplayed by its manufacturer, by giving a mean increase of only up to 3 mm Hg.  But this average downplays the important minority of patients who have notable increases in blood pressure. In persons with hypertension, it doesn’t make sense to use an antidepressant that worsens hypertension, when many other safer options are available.  

Other Risks

Venlafaxine is among the worst agents for causing serotonin withdrawal syndrome, presumably due to its short half-life, which is still the case with the XR formulation. This agent also causes mania at least twice as much as is the case with other SRIs, according to randomized trials. Thus, it shouldn’t be prescribed at all in bipolar depression.  


This agent is the active metabolite of venlafaxine. Sometimes, active metabolites can have different effects then the parent drug, but this does not seem to be the case with desvenlafaxine.  Except for some differences in dosing, all of the above benefits and harms apply to this agent as well.   

The PL Bottom Line

  • Venlafaxine is more of a standard SRI than anything else.   
  • It has many harms, especially major cardiac risks, and PL recommends that it not be used in patients with cardiac disease or hypertension. 
  • It has severe serotonin withdrawal syndrome and high risk of mania, and thus should not be used in bipolar illness. 

PL Reflection

In psychiatry, you can do biology in the morning and theology in the afternoon.

Robert Daly MD

courtesy of Ronald Pies MD

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