Venlafaxine works, but its edge over SSRIs is small, it can raise blood pressure and heart rate, and it has famously the worst withdrawal syndrome of any antidepressant. Some of us reach for it after SSRIs fail; others avoid starting it at all. Either way, never let it stop abruptly and taper slowly.
When we reach for it
When someone has failed SSRIs and you want a little more kick, venlafaxine over duloxetine. The data show it barely outperforms SSRIs, with a number needed to treat of about 24.
“I will go for venlafaxine over duloxetine when someone's failed SSRIs and I want a little bit more of a kick. Again, the data shows that it barely outperforms SSRIs. Number needed a treat of like 24 to outperform an SSRI”
27:45Anxiety Medications Tier List: The Best and Worst Treatments for GADJul 2026 Otherwise, go for an SNRI when there is a migraine disorder or diagnosed fibromyalgia. Not for apparent ADHD.
“I don't go for the SNRIs unless, as you say, they have a migraine disorder, a diagnosed fibromyalgia. I don't believe in it, by the way, for apparent ADHD”
41:09Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 Another view: do not use it at all unless the patient is already on it, because the withdrawal is so bad. An elderly woman once came in with what was basically delirium, and it turned out to be Effexor withdrawal.
“I actually don't use it at all unless someone is coming to me already on it because how bad the withdrawal is. You know, I remember a case where I saw elderly woman coming in for what was basically delirium and it ended up being because of Effexor withdrawal”
23:07Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025
Side effects and safety
Famously the worst withdrawal syndrome of all the antidepressants, severe enough to keep it out of a higher tier. An elderly patient was once medically hospitalized from it. It works well, but be careful and taper slowly.
“venlafaxine has a very severe withdrawal syndrome and paroxetine has plenty of weight gain, some anticholinergic, Even if it has to benefit”
25:17Anxiety Medications Tier List: The Best and Worst Treatments for GADJul 2026 Also said in 1 more episode
“Famously, the worst withdrawal syndrome out of all the antidepressants. I've even seen an elderly person get medically hospitalized once because of the withdrawal from venlafaxine. So it works well, but just be careful. You want to taper it slowly”
38:33Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 Stopping it abruptly can produce a withdrawal so bad it looks like a medical illness to the patient and caretakers, even with a little delirium.
“she decided to abruptly stop taking her Effexor a few days before. And the withdrawal syndrome was so bad it resembled a medical illness to her and to her caretakers and even caused a little delirium”
27:19Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025
Compared with others
Its improvement over SSRIs is relatively small, so it is not a big-hit medication, and it can raise blood pressure and heart rate.
“I don't like venlafaxine because its improvement over SSRIs is relatively small. So it's not like it's this big hit medication. It can raise blood pressure. It can raise heart rate”
39:53Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 SNRIs show only a very marginal improvement over SSRIs, if any, with slightly more side effects, and many patients have a really tough time getting off them, Effexor most of all.
“they're shown to have just a very marginal improvement in effect. And it's important to keep in mind that a lot of patients have a really tough time getting off of them. And especially with Effexor, withdrawal can be really, really difficult. So I think I like SNRIs a little bit less”
22:43Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025 Also said in 1 more episode
“I don't find that they have any efficacy over the SSRIs, and I find that they have slightly more side effects. Even if it's just slight blood pressure increase of the duloxetine, slightly more side effects. Another problem is Effexor is just an awful medication in terms of withdrawal syndrome. It's very strong and uncomfortable. So I avoid that entirely”
25:18Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 Desvenlafaxine theoretically has fewer drug-drug interactions than venlafaxine. No significant difference in efficacy between the two has been noticed.
“Desvenlafaxine theoretically has less drug-drug interactions than venlafaxine. I haven't noticed significant difference in terms of efficacy with the two medications”
44:54Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026
Pearls
You do not get the norepinephrine effect until a relatively high dose, which undercuts the point of choosing it.
“you don't even get the norepinephrine effect on Effexor until you get to a relatively higher dose. And so what's the point”
27:41Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025
It also comes up on
- MirtazapineMirtazapine plus venlafaxine is the famous California rocket fuel combination, coined by Stephen Stahl. Separately: if you are combining an SSRI with an SNRI, stop.
- SNRIsDo not combine an SSRI and an SNRI. Stop it. The famous combination in this family is California rocket fuel, which is mirtazapine plus venlafaxine.
From these episodes
- Anxiety Medications Tier List: The Best and Worst Treatments for GADJul 2026 · 2 points
- Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 · 4 points
- Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025 · 2 points
- Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 · 3 points
Every point above is something said on the Psychofarm podcast, with the words as spoken and a link to the moment in the episode. It is education, not medical advice, and an episode reflects what we thought when we recorded it.