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SNRIs (serotonin and noradrenaline reuptake inhibitors) are antidepressants that block the recycling of two chemical messengers, serotonin and noradrenaline. In the US, noradrenaline is called norepinephrine. SSRIs, by contrast, act mainly on serotonin. The two SNRIs most people in Ireland and the UK are offered are venlafaxine and duloxetine. Both are licensed for depression and generalised anxiety disorder. Duloxetine is also licensed for diabetic nerve pain.
In the largest comparison of antidepressants, both beat placebo by margins similar to other antidepressants. The practical differences are mostly about safety. Venlafaxine can raise blood pressure. Both can cause withdrawal symptoms if stopped suddenly. Both interact with St John's Wort and other serotonin-boosting products.
Everything below was checked against official sources in each market. For SSRIs, see our companion piece on what SSRIs actually do.
Nerve cells release serotonin and noradrenaline, then pull them back in through transporter proteins. SNRIs block both transporters, so both messengers stay active for longer. SSRIs mainly block the serotonin transporter.
The official product information says venlafaxine and its main breakdown product inhibit serotonin and noradrenaline reuptake, and weakly inhibit dopamine uptake. Duloxetine's says the same. That main breakdown product, O-desmethylvenlafaxine, is itself sold in the US as desvenlafaxine.
The noradrenaline action matters in two ways. The European Medicines Agency explains duloxetine's use in nerve pain by the role both messengers play in pain. Duloxetine's product information also says its noradrenaline effect may explain rises in blood pressure.
As with SSRIs, the transporter block starts quickly but any benefit takes weeks. For duloxetine in depression, response is usually seen after two to four weeks.
A few points the list can't hold:
The best single source is a 2018 network meta-analysis in The Lancet led by Andrea Cipriani. It pooled 522 double-blind trials with 116,477 adults with depression, across 21 antidepressants. "Response" meant at least a 50% fall in symptom score, measured as close to eight weeks as possible.
How to read it honestly:
The EMA's summary of duloxetine's depression trials says results varied, with duloxetine beating placebo in four of them. In two trials in children aged 7 to 17 with depression, neither duloxetine nor fluoxetine separated from placebo.
The ranked picture of all options, including therapy and exercise, is in depression: what actually works. For anxiety, see what actually works for anxiety.
Venlafaxine's product information says dose-related rises in blood pressure are commonly reported. Some severe rises needing immediate treatment have been reported since it came to market. Blood pressure should be checked before starting, and high blood pressure controlled first. It should then be reviewed periodically and after dose increases. Heart rate can rise too, particularly at higher doses.
The US label gives numbers from trials:
Duloxetine looks milder on average but is not exempt. In pooled US trials, average systolic pressure rose 0.23 mmHg and diastolic 0.73 mmHg, against small falls on placebo. Sustained rises were no more frequent than on placebo. However, hypertensive crisis has been reported, especially in people with existing high blood pressure. In Ireland and the UK, duloxetine must not be started in uncontrolled hypertension.
If you have high blood pressure or heart disease, tell your prescriber before starting either drug.
Withdrawal symptoms are a known feature of both drugs. In duloxetine trials, symptoms after stopping abruptly occurred in about 45% of people, versus 23% on placebo.
Across all antidepressants, a 2024 meta-analysis by Henssler and colleagues found symptoms in 31% after stopping a drug, and 17% after stopping placebo. Accounting for that, the authors estimated about 15% are attributable to the drug. Venlafaxine and desvenlafaxine were among those with more frequent and more severe symptoms. Estimates vary widely between studies; our SSRI piece covers that debate.
NICE singles out venlafaxine and paroxetine as more likely to cause withdrawal symptoms. It also says drugs with a short half-life need slower tapering. Venlafaxine's half-life is about 5 hours, and its active breakdown product's about 11. Duloxetine's averages 12.
Commonly reported symptoms include:
Symptoms usually start within a few days and usually settle within two weeks. In some people they last two to three months or more. NICE tells clinicians to reassure people with withdrawal symptoms that this is not their depression returning. Any reduction should be planned with your prescriber.
Serotonin syndrome is a potentially life-threatening reaction to too much serotonin activity. Signs include agitation, hallucinations, fast heartbeat, high temperature, overactive reflexes, poor coordination, and nausea, vomiting or diarrhoea. Seek urgent medical help if these appear.
The risk rises when SNRIs are combined with other serotonergic substances. Venlafaxine's product information lists:
MAOIs: combining either SNRI with an irreversible MAOI is not allowed. There must be at least 14 days after stopping an MAOI before starting either. Venlafaxine needs at least 7 days, and duloxetine at least 5, before an MAOI is started.
St John's Wort: the NHS says not to use it with either drug. NICE advises against prescribing or recommending it for depression, partly because of serious interactions. Our piece on St John's Wort's efficacy and interaction risk has the detail.
Tryptophan and 5-HTP: venlafaxine's product information says tryptophan supplements are not recommended with it. Duloxetine's advises caution. 5-HTP is the compound the body turns directly into serotonin. Neither leaflet names it, so the caution rests on that mechanism rather than trial data.
Duloxetine-specific: it must not be combined with fluvoxamine, ciprofloxacin or enoxacin. These block the enzyme that clears duloxetine; fluvoxamine raised duloxetine levels about sixfold.
A disclosure. Proco sells two products relevant here. Sleep Support contains St John's Wort and 5-HTP, in undisclosed amounts. Sleep Formula contains 100 mg of L-tryptophan. If you take an SNRI, check with your pharmacist before taking either. Our full list is in Proco products and mental health medication interactions.
In the US, the labels for venlafaxine, duloxetine, desvenlafaxine and levomilnacipran all carry a boxed warning. Antidepressants increased suicidal thoughts and behaviour in children, teenagers and young adults in short-term trials.
The FDA's pooled analysis covered about 77,000 adults and 4,500 children. Compared with placebo, per 1,000 people treated:
Whether the risk continues beyond about four months is unknown. Depression itself also raises suicide risk.
In Ireland and the UK, the product information says venlafaxine and duloxetine should not be used in under-18s. In the US, duloxetine is approved for generalised anxiety from age 7 and fibromyalgia from age 13.
For anyone aged 18 to 25 starting an antidepressant, NICE recommends a review after one week. The product information also warns that risk may rise early in recovery, and around dose changes. Tell your prescriber straight away about worsening mood, new suicidal thoughts, agitation or unusual changes in behaviour.
Not clearly. Duloxetine and venlafaxine had slightly higher odds ratios than sertraline or escitalopram, but the intervals overlapped. Choice usually depends on your history, other conditions and side effects.
Yes. In Ireland and the UK it is licensed for diabetic nerve pain. In the US it is also approved for fibromyalgia and chronic musculoskeletal pain. NICE includes it in its pain guidance.
Venlafaxine's product information advises against alcohol. The US duloxetine label says to avoid duloxetine in people with substantial alcohol use, because of liver risk. Ask your pharmacist what applies to you.
Talk to your prescriber first. Both drugs can cause withdrawal symptoms, and venlafaxine is singled out for this. NICE says the pace of any reduction should be agreed with you.
This article is general information, not medical advice. Do not start, stop or change any medicine without talking to your GP, prescriber or pharmacist.
Reviewed by: Proco Team
Last updated: November 2026