SNRIs are not stronger SSRIs: they show at most a marginal efficacy edge, slightly more side effects and, with venlafaxine especially, a hard withdrawal. We reach for them when there is a second target such as migraine, chronic pain or fibromyalgia, or after a partial SSRI response. Never stack an SSRI on an SNRI.
When we reach for it
Use an SNRI first line only when a comorbidity gives it a second job: a diagnosed migraine disorder or chronic pain with a good medical explanation that is not adequately treated, or fibromyalgia. Then you might as well use a dual-use medication. In some cases true ADHD counts, but not apparent ADHD. They may also be a little better for hot flashes.
“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 Also said in 3 more episodes
“I will do it first line if I see a comorbidity where there may be an indication. Chronic pain, migraine disorder. What I would caution, though, is that, oh, and in some cases, true ADHD. We're not going to get into that today”
23:48Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025 “I typically use it when it's got the comorbidities. Like you said, pain disorders, migraines, fibromyalgia. I think they're a little bit better in hot flashes”
24:19Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025 “Does this person have a migraine disorder that's been diagnosed and they're not getting enough treatment for? Does this person have a chronic pain issue that they have, there's a good medical explanation for, and that they're not getting adequately treated for? Then you might as well use a medication that's dual use there”
26:06Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 If someone did okay but not great on an SSRI (a little dent, not a big one), an SNRI is appropriate.
“if I saw someone do okay on an SSRI but not great and, you know, they failed too, and when I say failed, like you didn't see a huge dent but you saw a little bit, I think an SNRI is appropriate”
28:52Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025
Compared with others
We do not find SNRIs more effective than SSRIs (at most a very marginal improvement) and they have slightly more side effects, even if just duloxetine's slight blood pressure rise. Many patients have a really tough time getting off them, and venlafaxine's withdrawal is strong and uncomfortable enough that we avoid it entirely.
“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
Pitfalls and myths
Many prescribers assume an SNRI is a much stronger medication to reach for whenever something does not work. The number needed to treat versus an SSRI is actually pretty big, and it comes with risks and side effects.
“a lot of practitioners just assume SNRI is a much stronger medication that you should reach for whenever something doesn't work. The number needed to treat is actually pretty big regards to if you use an SNRI compared to an SSRI. And it comes with risks. It comes with side effects”
26:27Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 Do not combine an SSRI and an SNRI. Stop it. The famous combination in this family is California rocket fuel, which is mirtazapine plus venlafaxine.
“The combo that is a little famous is the California rocket fuel as coined by Stephen Stahl, which is mirtazapine and venlafaxine. Anyone who's using an SSRI and SNRI, stop it. Stop it”
42:08Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026
It also comes up on
- DuloxetineWhen someone has failed SSRIs and we want a little more of a kick, we go for venlafaxine over duloxetine, though the data show venlafaxine barely outperforms SSRIs (a number needed to treat of about 24).
- VenlafaxineWhen 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.
- AnxietyFor primary anxiety not responding to SSRIs and SNRIs, the traditional answer is tricyclics. For experienced or well-supervised clinicians at the end of the road, consider an MAOI.
- AugmentationFor someone on an adequately dosed SSRI or SNRI, add-on options include bupropion, mirtazapine and buspirone, and then the second-generation antipsychotics, which are very popular in the US but high risk.
- Bipolar disorderAvoid SSRIs, SNRIs and bupropion like the plague unless you cannot get away without them. If someone is already rock-solid stable on an antidepressant, that is fine.
- BuspironeFor an adequately dosed SSRI or SNRI that needs an add-on, buspirone sits alongside bupropion and mirtazapine. Second-generation antipsychotics are the popular but high-risk alternative.
- Generalized anxiety disorderReach for duloxetine with comorbid pain or fibromyalgia.
- Major depressive disorderVenlafaxine works well but has famously the worst withdrawal syndrome of the antidepressants (enough to hospitalize an elderly patient). Taper it slowly.
From these episodes
- Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 · 2 points
- Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025 · 3 points
- Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 · 4 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.