MVIIIHealth The MVIII app
← Back

Research · Medication

SNRIs

Meta-analyses found SNRIs raised response in depression and generalized anxiety more than placebo. Duloxetine 60 mg gave one extra person 50% pain relief for every 5 treated in diabetic nerve pain, with smaller effects in fibromyalgia and back pain. Nausea, raised blood pressure and stopping symptoms were reported. Labels carry a boxed warning on suicidal thoughts under 25.

Add to Bio HackChecked 2026-11-13
Status
Prescription drugs in the US. FDA-approved uses differ by drug: duloxetine for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia and chronic musculoskeletal pain. Venlafaxine extended release for major depressive disorder, generalized anxiety disorder, social anxiety disorder and panic disorder. Desvenlafaxine for major depressive disorder. No label cited here lists hot flashes or urinary incontinence.
Also called
serotonin-norepinephrine reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, duloxetine, Cymbalta, venlafaxine, Effexor, Effexor XR, desvenlafaxine, Pristiq
Taken for
depression, anxiety, panic attacks, social anxiety, nerve pain, diabetic neuropathy, fibromyalgia, chronic back pain, osteoarthritis pain, hot flashes, stress urinary incontinence

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help9

Reported risks22

What people take it for, and what was found

Shown to help9

Strong

Depression in adults

Shown to raise response in adult depression more than placebo. Head-to-head trials placed venlafaxine among the higher response rates and duloxetine level with other antidepressants.

The numbers and sources
Effect
Across 522 trials of 21 antidepressants, every drug had a higher response rate than placebo, with odds ratios from 1.37 to 2.13 and a summary standardized mean difference of 0.30 (95% CrI 0.26 to 0.34). In head-to-head trials, venlafaxine was among the drugs with higher response rates, and duloxetine and venlafaxine were among those with the most dropouts [1]. An earlier meta-analysis of 32 trials found venlafaxine ahead of other antidepressants by a standardized effect size of 0.14 (95% CI 0.07 to 0.22), with a similar margin over SSRIs [2]. Duloxetine did not differ from other antidepressants in a Cochrane review of 16 trials [3]. Desvenlafaxine at 50 to 400 mg a day lowered depression scores more than placebo in 8 trials [4]. For venlafaxine, response rose with dose up to about 75 to 150 mg, with a smaller rise above that [5].
Population
116,477 adults in 522 trials [1]; 32 randomized trials of venlafaxine [2]; 5,735 participants in 16 trials of duloxetine against other antidepressants [3]; 8 RCTs of desvenlafaxine [4]; 19,364 participants in 77 dose-finding studies [5].
Sources
[1], [2], [3], [4], [5]
Caveats
The headline figures in [1] cover all antidepressant classes, and its certainty of evidence ranged from moderate to very low. The abstract of [4] gives no effect size. Most trials lasted weeks.
StrongVery common

Generalized anxiety disorder

Shown to lower anxiety scores in generalized anxiety disorder, by about 3.1 Hamilton points more than placebo on duloxetine and 2.7 on venlafaxine.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In a network meta-analysis, duloxetine lowered Hamilton Anxiety scores more than placebo (MD -3.13, 95% CrI -4.13 to -2.13), as did venlafaxine (MD -2.69, 95% CrI -3.50 to -1.89) [6]. Across antidepressants, response was more likely than on placebo (RR 1.41, 95% CI 1.29 to 1.55), a number needed to treat of 7 (95% CI 5 to 9), with similar findings when classes were compared separately. Dropouts for adverse effects were more frequent (RR 2.18), a number needed to harm of 17 [7]. Across anxiety, obsessive-compulsive and stress disorders, SSRIs and SNRIs lowered symptoms against placebo (SMD -0.56, 95% CI -0.62 to -0.51) [8].
Population
25,441 adult outpatients in 89 trials [6]; 12,226 adults in 37 RCTs of 4 to 28 weeks [7]; 30,245 adults and children in 135 studies [8].
Sources
[6], [7], [8], [9]
Caveats
[7] pooled SNRIs with other antidepressants. Desvenlafaxine has no generalized anxiety approval on its label [9].
Moderate

Social anxiety and panic disorder

Shown to reduce social anxiety and panic symptoms more than placebo in the venlafaxine trials behind its approval, five in social anxiety and two in panic disorder.

The numbers and sources
Effect
The evidence here is for venlafaxine extended release. In five placebo-controlled studies in social anxiety disorder, it lowered Liebowitz Social Anxiety Scale scores more than placebo, by about 14 points in the 6-month study, with no added benefit at 150 to 225 mg over 75 mg. In two 12-week studies in panic disorder, more patients were free of full panic attacks and rated as responders than on placebo at each dose [10]. A Cochrane review found venlafaxine reduced social anxiety symptoms and had more treatment withdrawals than placebo (RR 3.23, 95% CI 2.15 to 4.86) [11]. In panic disorder, antidepressants as a group lowered the risk of not responding (RR 0.72, 95% CI 0.66 to 0.79), and the finding held for each class [12].
Population
Adult outpatients in five social anxiety studies and two panic disorder studies [10]; 1,213 adults in 4 venlafaxine trials for the withdrawal outcome [11]; 8,252 adults with panic disorder in 41 RCTs [12].
Sources
[10], [11], [12]
Caveats
The label gives placebo-subtracted scores but no responder rates for social anxiety. Duloxetine and desvenlafaxine are not approved for either condition.
StrongVery common

Diabetic nerve pain

Shown to cut pain by half or more in painful diabetic neuropathy on duloxetine 60 mg, with about 5 treated for one extra person helped.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
The evidence is for duloxetine. At 60 mg a day, a 50% or greater drop in pain at 12 weeks was more likely than on placebo (RR 1.73, 95% CI 1.44 to 2.08), a number needed to treat of 5 (95% CI 4 to 7). Doses of 60 and 120 mg both reduced pain, and lower doses did not. 16% of participants stopped the drug for adverse effects [13]. Across neuropathic pain conditions, the combined number needed to treat for SNRIs was 6.4 (95% CI 5.2 to 8.4), with duloxetine making up 9 of 14 studies [14]. In a network meta-analysis of chronic pain, duloxetine was the highest-ranked antidepressant, and 60 mg did as well as higher doses on most outcomes [15].
Population
2,728 participants with painful diabetic neuropathy in 8 studies [13]; 229 studies of drugs for neuropathic pain in adults [14]; 28,664 adults with chronic pain in 176 studies averaging 10 weeks [15].
Sources
[13], [14], [15]
Caveats
Almost every duloxetine study was run or sponsored by the manufacturer [13]. An analysis of publication bias suggested treatment effects in neuropathic pain were overstated by about 10% [14]. Most studies measured short-term outcomes only [15].
StrongCommon

Fibromyalgia

Shown to raise the share with 50% pain relief in fibromyalgia from about 21% to 31%, a gain Cochrane reviewers judged not clinically relevant.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
On duloxetine or milnacipran, 31% reported pain relief of 50% or greater against 21% on placebo (risk difference 0.09, 95% CI 0.07 to 0.11), a number needed to treat of 11. More people rated themselves much or very much improved (52% vs 29%, number needed to treat 5). Fatigue changed little (SMD -0.13) [16]. For duloxetine 60 mg alone, the risk ratio for 50% pain relief was 1.57 (95% CI 1.20 to 2.06) at 12 weeks, a number needed to treat of 8 [13]. Across chronic pain conditions, with fibromyalgia the most studied, duloxetine 60 mg raised the odds of substantial pain relief (OR 1.91, 95% CI 1.69 to 2.17) [15].
Population
7,903 participants in 18 studies, 7 of duloxetine, 9 of milnacipran and 1 of desvenlafaxine [16]; 2,249 participants with fibromyalgia in 6 studies [13]; 4,490 participants in 16 studies for the pain relief outcome [15].
Sources
[16], [13], [15]
Caveats
Evidence quality was rated low for all comparisons with placebo, over concerns about publication bias [16]. The pooled figures mix duloxetine with milnacipran, which is outside this page. The band above uses the 9 to 10 point gain in responders.
Moderate

Chronic back pain and osteoarthritis pain

Shown to lower back pain by about 5 points on a 100-point scale, which reviewers called not clinically important, and osteoarthritis pain by about 10 points.

The numbers and sources
Effect
On a scale from 0 to 100, SNRIs lowered back pain by 5.30 points more than placebo at 3 to 13 weeks (95% CI 3.30 to 7.31) and osteoarthritis pain by 9.72 points (95% CI 6.69 to 12.75). Back pain disability fell by 3.55 points. The authors judged the back pain effect small and not clinically important, and could not exclude a clinically important effect in osteoarthritis [17]. Across chronic pain conditions, duloxetine 60 mg lowered pain intensity against placebo (SMD -0.31, 95% CI -0.39 to -0.24) [15].
Population
5,318 participants with back pain, sciatica or osteoarthritis in 33 trials [17]; 4,959 participants in 18 studies for pain intensity [15].
Sources
[17], [15], [18]
Caveats
Certainty was moderate for back pain and low for osteoarthritis [17]. Duloxetine is the only SNRI with a chronic musculoskeletal pain approval [18]. Most trials were short and excluded people with low mood [15].
ModerateStudied in women

Menopausal hot flashes

Shown to reduce moderate and severe hot flashes in postmenopausal women on desvenlafaxine 100 mg, an unapproved use. Venlafaxine lowered hot flash scores in women with breast cancer.

The numbers and sources
Effect
In six placebo-controlled trials, desvenlafaxine 100 mg lowered the frequency of moderate and severe hot flashes at week 12 (SMD -0.49, 95% CI -0.91 to -0.07), as did 150 mg (SMD -0.36, 95% CI -0.54 to -0.19) [19]. In women treated for breast cancer, venlafaxine at 75 mg a day or more lowered hot flash scores against non-hormonal comparators (SMD 2.06, 95% CI 0.40 to 3.72) [20].
Population
Postmenopausal women with moderate to severe hot flashes in 6 RCTs [19]; women treated for breast cancer in randomized trials of venlafaxine [20].
Sources
[19], [20]
Caveats
No SNRI label cited here lists hot flashes. The venlafaxine analysis had very high heterogeneity (I² 98.7%) and signs of publication bias, and its comparators were other non-hormonal treatments [20].
ModerateStudied in womenVery common

Stress urinary incontinence

Shown to reduce weekly leaks in women by about 14 percentage points more than placebo on duloxetine, with one in seven stopping for side effects.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In clinical study reports for duloxetine, weekly incontinence episodes fell 13.56 percentage points more than on placebo (95% CI 5.53 to 21.59). The number needed to treat for feeling much or very much better was 8 (95% CI 6 to 13). The number needed to harm was 7 for stopping because of an adverse event and 7 for what the authors called an activation event. The authors concluded the harms outweighed the benefits [21].
Population
Women with stress urinary incontinence in placebo-controlled trials analyzed from clinical study reports [21].
Sources
[21]
Caveats
Not an approved use in the US. The abstract does not give the number of trials or women [21].
LimitedVery common

Nerve pain after chemotherapy

One trial found duloxetine lowered pain from chemotherapy nerve damage by 0.73 points more than placebo on a 10-point scale over 5 weeks.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Average pain fell by 1.06 points on duloxetine and 0.34 on placebo, a difference of 0.73 (95% CI 0.26 to 1.20) on a scale of 0 to 10. Any decrease in pain was reported by 59% on duloxetine and 38% on placebo [22].
Population
231 adults with painful neuropathy after taxane or oxaliplatin chemotherapy, in a crossover trial of 30 mg for one week then 60 mg for four weeks [22].
Sources
[22]
Caveats
One trial of 5 weeks per period. Not an approved use.

Not shown to help2

ModerateStudied in children

Depression in children and teenagers

Not shown to reduce depression more than placebo in children and teenagers on venlafaxine or desvenlafaxine. Duloxetine showed a small reduction in low-certainty evidence.

The numbers and sources
Effect
In a network meta-analysis of 14 antidepressants, only fluoxetine reduced symptoms more than placebo, and venlafaxine (OR 3.19) and duloxetine (OR 2.80) had more discontinuations for adverse events than placebo [23]. In a Cochrane network meta-analysis on a scale running from 17 to 113, desvenlafaxine did not differ from placebo (MD -0.07, 95% CI -3.51 to 3.36), and duloxetine lowered scores by 2.70 points (95% CI 0.37 to 5.03) in low-certainty evidence. Venlafaxine was associated with higher odds of suicide-related outcomes than placebo (OR 13.84, 95% CI 1.79 to 106.90) [24].
Population
5,260 children and adolescents in 34 trials [23]; 26 studies in children and adolescents [24].
Sources
[23], [24], [10], [9]
Caveats
The interval for the venlafaxine suicide-related estimate is very wide. The Cochrane authors described the symptom reductions for most antidepressants as small and unimportant [24]. Venlafaxine and desvenlafaxine are not approved for use in pediatric patients [10][9].
Moderate

Differences between SNRIs

Not shown to differ in depression response between duloxetine and venlafaxine or desvenlafaxine in four trials. More people dropped out on duloxetine than on venlafaxine.

The numbers and sources
Effect
Four studies compared duloxetine with venlafaxine (three) or desvenlafaxine (one) and found no statistically significant differences in efficacy. Dropout for any cause was more frequent on duloxetine than on venlafaxine (OR 1.56, 95% CI 1.14 to 2.15) and than on the SSRI escitalopram (OR 1.62, 95% CI 1.01 to 2.62) [3].
Population
1,978 participants in 4 studies comparing duloxetine with another SNRI [3].
Sources
[3]
Caveats
Few trials per comparison, with wide pooled intervals [3].

Doses studied

The duloxetine label lists 40 to 60 mg a day for depression and 60 mg once daily for generalized anxiety, diabetic nerve pain, fibromyalgia and chronic musculoskeletal pain. It states that 120 mg a day was studied and that there is no evidence doses above 60 mg add benefit [18]. The Cochrane pain review found 60 and 120 mg reduced diabetic nerve pain and lower doses did not [13]. The chemotherapy neuropathy trial used 30 mg for one week and then 60 mg [22].

The venlafaxine extended release label describes studies at 37.5 to 225 mg a day, with 75 mg a day as the target dose for each approved use [10]. A dose-response meta-analysis found venlafaxine's effect on depression rose up to about 75 to 150 mg, with dropouts lowest in the lower licensed range [5]. The desvenlafaxine label lists 50 mg once daily, studied up to 400 mg, and states there was no evidence that doses above 50 mg add benefit [9]. The hot flash trials used desvenlafaxine 100 and 150 mg [19].

Risks

Reported risks19

ModerateVery common

Nausea and other common side effects

Shown to raise nausea, dry mouth, sweating, constipation and dizziness against placebo, with nausea in 23% to 30% against 8% to 12% on placebo.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In pooled duloxetine trials: nausea 23% vs 8% on placebo, dry mouth 13% vs 5%, constipation 9% vs 4%, dizziness 9% vs 5%, fatigue 9% vs 5%, decreased appetite 7% vs 2% and sweating 6% vs 1% [18]. In pooled venlafaxine extended release trials: nausea 30.0% vs 11.8%, dizziness 15.8% vs 9.5%, dry mouth 14.8% vs 5.3%, sweating 11.4% vs 2.9%, loss of appetite 9.8% vs 2.6% and constipation 9.3% vs 3.4% [10]. On desvenlafaxine, nausea rose with dose, from 22% at 50 mg to 41% at 400 mg, against 10% on placebo [9]. In pain trials, 16% stopped duloxetine for adverse effects [13].
Population
8,100 adults on duloxetine and 5,655 on placebo [18]; 3,558 adults on venlafaxine extended release and 2,197 on placebo in studies up to 12 weeks [10]; adults in short-term desvenlafaxine depression studies [9]; 6,407 participants in 18 pain trials [13].
Sources
[18], [10], [9], [13]
Caveats
Short-term trials. Several of these effects were dose-dependent [18][9].
StrongVery common

Insomnia and drowsiness

Shown to raise both insomnia and drowsiness against placebo, with insomnia in 18% on venlafaxine against 10% and drowsiness in 15% against 8%.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In pooled venlafaxine extended release trials, insomnia occurred in 17.8% vs 9.5% on placebo, somnolence in 15.3% vs 7.5% and abnormal dreams in 2.9% vs 1.4% [10]. In pooled duloxetine trials, somnolence occurred in 10% vs 3% and insomnia in 9% vs 5% [18]. A network meta-analysis of 216 trials found 13 of 21 antidepressants had higher odds of somnolence than placebo and 11 had higher odds of insomnia [27]. An earlier meta-analysis found the highest incidence of insomnia with bupropion and desvenlafaxine [28].
Population
Adults in pooled label trials [10][18]; 64,696 patients with depression in 216 trials [27]; trials of second-generation antidepressants in depression [28].
Sources
[10], [18], [27], [28]
Caveats
The two meta-analyses cover all newer antidepressants. Evidence quality was rated very low to moderate [27].
StrongVery common

Symptoms after stopping

Shown to cause discontinuation symptoms in about 31% of people stopping an antidepressant against 17% stopping placebo, with venlafaxine and desvenlafaxine among the most frequent.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
At least one discontinuation symptom occurred in 31% (95% CI 27 to 35) after stopping an antidepressant and 17% (95% CI 14 to 21) after stopping placebo, a difference of 8 percentage points within randomized trials. Severe symptoms occurred in 2.8% vs 0.6%. Desvenlafaxine and venlafaxine were among the drugs with higher frequency and higher severity [29]. A second meta-analysis found about one more symptom in the first week after stopping (SMD 0.31, 95% CI 0.23 to 0.39), with dizziness the most frequent (OR 5.52, risk difference 6.24%) [30]. A systematic review of 61 SNRI reports found withdrawal symptoms after every SNRI, a prevalence that varied between reports and appeared higher with venlafaxine, onset within a few days, and a course of a few weeks, including after gradual tapering [31]. The venlafaxine label states that symptom frequency rose with dose and with length of treatment [10]. The desvenlafaxine label reports postmarketing cases that were protracted and severe [9].
Population
21,002 patients in 79 studies [29]; 17,828 participants in 50 studies [30]; 22 randomized trials, 16 other studies and 23 case reports of SNRIs [31].
Sources
[29], [30], [31], [10], [9]
Caveats
The pooled rates combine SNRIs with other antidepressants, and heterogeneity was substantial [29]. The SNRI review gives no pooled rate [31].
ModerateCommon

FDA boxed warning: suicidal thoughts and behaviors in young people

FDA states antidepressants raised suicidal thoughts and behaviors in pediatric and young adult patients in short-term trials, 14 more cases per 1,000 under age 18.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Every SNRI label carries this boxed warning. In FDA's pooled analyses of placebo-controlled antidepressant trials, the difference between drug and placebo in cases of suicidal thoughts or behaviors per 1,000 patients treated was 14 more under age 18, 5 more at ages 18 to 24, 1 fewer at ages 25 to 64 and 6 fewer at 65 and older [18]. In the pediatric analysis, the risk ratio for all drugs across all indications was 1.95 (95% CI 1.28 to 2.98), a risk difference of 0.02 [25]. In adults with psychiatric indications, the odds ratio for suicidal behavior or ideation was 1.62 (95% CI 0.97 to 2.71) under age 25, 0.79 (95% CI 0.64 to 0.98) at 25 to 64 and 0.37 (95% CI 0.18 to 0.76) at 65 and older [26]. In a Cochrane analysis of pediatric depression trials, venlafaxine had higher odds of suicide-related outcomes than placebo (OR 13.84, 95% CI 1.79 to 106.90) [24].
Population
Placebo-controlled trials of SSRIs and other antidepressants in adults and pediatric patients pooled by FDA [18][25][26]; 26 pediatric depression studies [24].
Sources
[18], [25], [26], [24]
Caveats
The label reports differences from placebo, not absolute rates, so the band above is the excess under age 18. The trials were short. The outcome was thoughts and behaviors, and no suicides occurred in the pediatric trials [18].
ModerateCommon

Raised blood pressure

Shown to raise blood pressure in a dose-related way, with sustained hypertension in about 1% to 3% on venlafaxine or desvenlafaxine against 0.5% on placebo.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
On venlafaxine extended release, sustained diastolic hypertension occurred in 3% of people in depression studies at 75 to 375 mg a day and in 0.5% to 0.9% in anxiety and panic studies. A diastolic rise of 15 mm Hg or more to at least 105 mm Hg occurred in 1.4% vs 0.9% on placebo [10]. On desvenlafaxine, sustained hypertension occurred in 1.3% at 50 mg and 2.3% at 400 mg against 0.5% on placebo [9]. In original data from depression trials, venlafaxine's effect on diastolic pressure was highly dose dependent and reached significance only above 300 mg a day [32]. On duloxetine, mean blood pressure rose 0.5 mm Hg systolic and 0.8 diastolic against small falls on placebo, and sustained elevations did not differ from placebo [18].
Population
Adults in premarketing studies of venlafaxine extended release [10] and desvenlafaxine [9]; 3,744 patients with depression [32]; adults in placebo-controlled duloxetine trials [18].
Sources
[10], [9], [32], [18]
Caveats
Short-term studies. The venlafaxine label notes too few people took more than 300 mg a day to measure the rate at those doses [10].
ModerateCommon

Sexual side effects

Shown to raise sexual side effects on venlafaxine and duloxetine, with abnormal ejaculation or orgasm in about 10% of men on venlafaxine against 0.5% on placebo.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In pooled venlafaxine extended release trials, men reported abnormal ejaculation or orgasm (9.9% vs 0.5% on placebo), impotence (5.3% vs 1.0%) and anorgasmia (3.6% vs 0.1%), women reported anorgasmia (2.0% vs 0.2%), and decreased libido occurred in 5.1% vs 1.6% overall [10]. In duloxetine depression and anxiety trials, erectile dysfunction occurred in 4% vs 1% and decreased libido in 3% vs 1% [18]. A meta-analysis that included studies asking about sexual function directly found venlafaxine and duloxetine among the drugs with more sexual dysfunction than placebo, with rates of 25.8% to 80.3% across those drugs [33]. In three desvenlafaxine trials using a sexual function scale, dysfunction rates were 54% at 50 mg, 47% at 100 mg and 49% on placebo, with no overall difference [34].
Population
1,440 men and 2,118 women on venlafaxine extended release [10]; adults in duloxetine trials [18]; antidepressant studies pooled by drug [33]; 1,562 adults with depression in 3 trials [34].
Sources
[10], [18], [33], [34]
Caveats
The band above is from label trials, which rely on spontaneous reports. Studies that asked directly found higher rates [33]. The desvenlafaxine analysis was post hoc [34].
ModerateCommon

Liver injury

Shown to raise liver enzymes on duloxetine, with ALT above 3 times the upper limit in 1.25% against 0.45% on placebo. Liver failure has been reported.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In adult placebo-controlled duloxetine trials, ALT rose above 3 times the upper limit of normal in 1.25% (144 of 11,496) on duloxetine and 0.45% (39 of 8,716) on placebo, with a dose-response relationship in fixed-dose studies. Liver enzyme rises led 0.3% (92 of 34,756) to stop the drug. The label also reports cases of hepatic failure, some fatal, and cholestatic jaundice [18].
Population
Adults in duloxetine clinical trials for any indication, and postmarketing reports [18].
Sources
[18]
Caveats
The evidence in this block is for duloxetine only. The serious cases come from reports with no denominator.
ModerateCommon

Low sodium

Linked to low blood sodium in about 6% of SNRI users in observational studies, at about twice the odds of non-users.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Across 38 observational studies, hyponatremia occurred in 6.13% of people on SNRIs, with an odds ratio of 2.270. Venlafaxine ranked highest among SNRIs and duloxetine lower [38]. An earlier review found incidence figures from 0.08% to 70% for venlafaxine depending on study design and cutoff, and named older age and thiazide diuretics as risk factors [39].
Population
30 cohort and 8 case-control studies [38]; 21 effect studies and more than 100 case reports [39].
Sources
[38], [39]
Caveats
Observational, with rates that swing widely by population and sodium cutoff. The abstract of [38] gives no confidence intervals.
LimitedUncommon

Mania or hypomania

The venlafaxine label reports mania or hypomania in 0.3% of people in depression studies against 0.0% on placebo.

The numbers and sources
How common
Uncommon: between 1 in 1,000 and 1 in 100 people.
Effect
In premarketing studies of venlafaxine extended release, mania or hypomania was reported in 0.3% vs 0.0% on placebo in depression, 0.0% vs 0.2% in generalized anxiety, 0.2% vs 0.0% in social anxiety and 0.1% vs 0.0% in panic disorder [10].
Population
Adults in premarketing studies of venlafaxine extended release [10].
Sources
[10]
Caveats
Small numbers of events, in trials that generally left out people with bipolar disorder.
LimitedRare

Use with triptans

Linked to serotonin syndrome rarely: 2 definite cases in 30,928 person-years of triptans taken with an SSRI or SNRI in one health system.

The numbers and sources
How common
Rare: fewer than 1 in 1,000 people.
Effect
Among 19,017 people prescribed a triptan together with an SSRI or SNRI, serotonin syndrome was classed as definite in 2, an incidence of 0.6 cases per 10,000 person-years (95% CI 0.0 to 1.5), and 2.3 per 10,000 when 5 possible cases were added [37]. The duloxetine label names triptans among the drugs that increase the risk [18].
Population
19,017 patients in one US health system over 14 years [37].
Sources
[37], [18]
Caveats
One records-based study that did not separate SNRIs from SSRIs.
LimitedHow often is not known

Dizziness on standing, fainting and falls

The duloxetine label reports falls, fainting and blood pressure drops on standing, with more falls than placebo across its trials. It gives no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label states that orthostatic hypotension, falls and syncope have been reported at the labeled doses, mostly in the first week or after a dose increase, and that people on duloxetine reported a higher rate of falls than people on placebo in an analysis of all placebo-controlled trials. It states the risk rose with age and that falls with fractures and hospital stays have been reported. It names blood pressure medicines and doses above 60 mg as raising the chance of a pressure drop [18].
Population
Adults in placebo-controlled duloxetine trials, as summarized in labeling [18].
Sources
[18]
Caveats
The label gives no fall rates for either group.
LimitedHow often is not known

Bleeding

Linked to bleeding after childbirth at about 1.5 times the rate in one cohort of duloxetine use. Labels warn the class may raise bleeding risk.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In a US cohort, duloxetine exposure late in pregnancy was associated with postpartum hemorrhage (RR 1.53, 95% CI 1.08 to 2.18), against a base risk of 23.3 per 1,000 unexposed women [36]. The labels state that drugs interfering with serotonin reuptake may increase the risk of bleeding events, from bruising and nosebleeds to life-threatening hemorrhage, and cite case reports and epidemiological studies of gastrointestinal bleeding [18][10].
Population
Pregnancies in a US insurance database, about 900 to 950 with late exposure to duloxetine [36].
Sources
[36], [18], [10]
Caveats
One observational cohort. The sources give no absolute rate in people taking an SNRI. No meta-analysis of bleeding limited to SNRIs was located.
LimitedHow often is not known

Bleeding with NSAIDs, aspirin and blood thinners

The labels warn that NSAIDs, aspirin, warfarin and other anticoagulants may add to bleeding risk, and report increased bleeding with warfarin. They give no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The duloxetine label states that epidemiological studies linking serotonin reuptake drugs to upper gastrointestinal bleeding also showed that an NSAID or aspirin taken at the same time may potentiate the risk, and that altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are taken with warfarin [18]. The venlafaxine label names aspirin, NSAIDs, warfarin and other anticoagulants as adding to the risk [10].
Population
Labeling statements drawn from epidemiological studies and reports [18][10].
Sources
[18], [10]
Caveats
No rate is given, and the studies cited by the labels mostly concern SSRIs.
LimitedHow often is not known

Serotonin syndrome

The label warns that SNRIs can cause serotonin syndrome, more often with other serotonergic drugs. It gives no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The duloxetine label states that taking it with other serotonergic drugs increases the risk of serotonin syndrome. It names other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan and St. John's Wort [18].
Population
Labeling statement [18].
Sources
[18]
Caveats
A label warning with no denominator.
LimitedHow often is not known

Use with MAOIs

The label lists MAOIs as a contraindication, within 14 days before or 5 days after duloxetine, because of an increased risk of serotonin syndrome.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The duloxetine label lists as contraindications taking it with an MAOI antidepressant, taking it within 14 days of stopping one, and starting an MAOI within 5 days of stopping duloxetine. It also lists starting duloxetine in a person being treated with the antibiotic linezolid or intravenous methylene blue [18].
Population
Labeling statement [18].
Sources
[18]
Caveats
The label gives no rate.
LimitedHow often is not known

Heart rhythm

The venlafaxine label reports QT prolongation and ventricular arrhythmias in postmarketing use, and a small rise in pulse in trials. It gives no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The venlafaxine label lists QT prolongation, ventricular fibrillation and ventricular tachycardia, including torsade de pointes, among reactions reported after approval. In depression studies, mean pulse rose about 2 beats a minute on venlafaxine and 1 on placebo. On desvenlafaxine, mean pulse rose 1.3 beats a minute at 50 mg and 4.1 at 400 mg against a fall of 0.3 on placebo [10][9].
Population
Postmarketing reports and premarketing studies summarized in labeling [10][9].
Sources
[10], [9]
Caveats
Voluntary reports from a population of unknown size.
LimitedHow often is not known

Overdose

The venlafaxine label reports that overdose may carry a higher risk of death than SSRI overdose and a lower risk than tricyclic overdose.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label cites published retrospective studies in which venlafaxine overdose was associated with more fatal outcomes than SSRI overdose and fewer than tricyclic overdose. It adds that people prescribed venlafaxine had more suicide risk factors than people prescribed SSRIs, so it is unclear how much of the difference comes from the drug [10].
Population
Retrospective studies summarized in labeling [10].
Sources
[10]
Caveats
The label gives no numbers and says the cause of the difference is not clear.
LimitedHow often is not known

Trouble passing urine

The duloxetine label reports cases of urinary retention after approval, some needing a hospital stay or a catheter. It gives no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label states that duloxetine belongs to a class of drugs known to affect urethral resistance and that cases of urinary retention have been observed in postmarketing experience [18].
Population
Postmarketing reports summarized in labeling [18].
Sources
[18]
Caveats
No denominator.
LimitedHow often is not known

Changed drug levels with other medicines

The duloxetine label reports a 6-fold rise in its blood levels with fluvoxamine, and a 3-fold rise in desipramine levels when taken with duloxetine.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
With fluvoxamine, a strong inhibitor of the enzyme CYP1A2, duloxetine exposure rose about 6-fold in 14 men. The label names cimetidine and the quinolone antibiotics ciprofloxacin and enoxacin as other inhibitors of that enzyme. Paroxetine raised duloxetine exposure by about 60%. Duloxetine itself is a moderate inhibitor of CYP2D6 and raised exposure to the antidepressant desipramine 3-fold [18].
Population
Volunteers in drug interaction studies described in labeling [18].
Sources
[18]
Caveats
These are changes in drug levels in small studies, not rates of harm. The block covers duloxetine only.

Mixed results3

ModerateCommon

Weight change

Mixed results: short trials showed appetite and weight loss, about 1 kg less than placebo in children, while six-month records showed slightly more gain than sertraline.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Loss of appetite was reported by 9.8% on venlafaxine extended release vs 2.6% on placebo [10] and by 7% on duloxetine vs 2% [18]. In adults on desvenlafaxine, mean weight change ran from -0.4 kg at 50 mg to -1.1 kg at 400 mg against 0.0 kg on placebo [9]. In children and teenagers, weight fell 0.1 kg on duloxetine over 10 weeks against a 0.9 kg gain on placebo, and 16% vs 6% lost 3.5% or more of body weight [18]. In health records, estimated 6-month weight gain was higher than on sertraline for duloxetine (0.34 kg, 95% CI 0.22 to 0.44) and venlafaxine (0.17 kg, 95% CI 0.03 to 0.31) [35].
Population
Adults and pediatric patients in label trials [10][18][9]; adults starting one of 8 antidepressants in US health systems [35].
Sources
[10], [18], [9], [35]
Caveats
The band above is the adult rate of appetite loss. [35] is observational, compared drugs with each other and had 6-month adherence of 28% for duloxetine.
ModerateUncommon

Pregnancy and newborns

Mixed results: major birth defects were not clearly raised with venlafaxine or duloxetine, while newborn lung pressure problems and bleeding after delivery were linked to exposure.

The numbers and sources
How common
Uncommon: between 1 in 1,000 and 1 in 100 people.
Effect
In 8 cohort studies, first-trimester venlafaxine exposure had a relative risk for major malformations of 1.12 (95% CI 0.92 to 1.35) and duloxetine 0.80 (95% CI 0.46 to 1.29) [40]. In a US cohort, duloxetine had a relative risk of 1.11 (95% CI 0.93 to 1.33) for malformations overall, 1.29 (95% CI 0.99 to 1.68) for cardiovascular malformations, 1.19 (95% CI 1.04 to 1.37) for preterm birth with late exposure and 1.53 (95% CI 1.08 to 2.18) for postpartum hemorrhage [36]. Among pregnancies exposed to an SSRI or SNRI, persistent pulmonary hypertension of the newborn occurred in 2.9 per 1,000 live births (OR 1.82, 95% CI 1.31 to 2.54) [41].
Population
3,186 infants exposed to venlafaxine and 668 to duloxetine [40]; cohorts of 1.3 to 4.1 million pregnancies with about 2,500 to 3,000 early duloxetine exposures [36]; 156,978 exposed pregnancies in 11 studies [41].
Sources
[40], [36], [41]
Caveats
Observational. The duloxetine data are small, and [41] did not separate SNRIs from SSRIs. The band above is the newborn pulmonary hypertension rate.
LimitedHow often is not known

Alcohol

Mixed results: one study found duloxetine did not add to impairment from alcohol, while three trial patients with liver injury were heavy drinkers.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
When duloxetine and alcohol were given so that their peak levels coincided, duloxetine did not increase the impairment of mental and motor skills caused by alcohol. In the clinical trials database, three people on duloxetine had liver injury with raised ALT and bilirubin, each with substantial alcohol use. The label states duloxetine and alcohol may interact to cause liver injury [18].
Population
Volunteers in an interaction study and three cases from the duloxetine trials database [18].
Sources
[18]
Caveats
Three cases cannot show cause. The label does not give the size of the interaction study.

Claims tested and not found

  1. That doses above the standard dose add benefit. A Cochrane network meta-analysis found standard-dose duloxetine did as well as high-dose duloxetine on most pain outcomes [15]. The labels state there is no evidence that duloxetine above 60 mg a day or desvenlafaxine above 50 mg a day adds benefit [18][9].
  2. That duloxetine outperforms other antidepressants for depression. In 16 head-to-head trials, efficacy did not differ, and more people dropped out on duloxetine than on escitalopram or venlafaxine [3].
  3. That SNRIs relieve back pain to a clinically important degree. Across trials, the reduction was 5.30 points on a 100-point scale, which the authors judged small and not clinically important [17].
  4. That duloxetine relieves central neuropathic pain. A single small trial in a Cochrane review found no effect [13].

Sources

  1. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet. 2018. https://doi.org/10.1016/S0140-6736(17)32802-7
  2. Smith D, Dempster C, Glanville J, et al. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: A meta-analysis. British Journal of Psychiatry. 2002. https://doi.org/10.1192/bjp.180.5.396
  3. Cipriani A, Koesters M, Furukawa TA, et al. Duloxetine versus other anti-depressive agents for depression. Cochrane Database of Systematic Reviews. 2012. https://doi.org/10.1002/14651858.CD006533.pub2
  4. Li L, Ren X, Yuan C. Efficacy and safety of desvenlafaxine in treating patients with major depressive disorder: a network meta-analysis. Frontiers in Neuroscience. 2026. https://doi.org/10.3389/fnins.2026.1721852
  5. Furukawa TA, Cipriani A, Cowen PJ, et al. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis. The Lancet Psychiatry. 2019. https://doi.org/10.1016/S2215-0366(19)30217-2
  6. Slee A, Nazareth I, Bondaronek P, et al. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. The Lancet. 2019. https://doi.org/10.1016/S0140-6736(18)31793-8
  7. Kopcalic K, Arcaro J, Pinto A, et al. Antidepressants versus placebo for generalised anxiety disorder (GAD). Cochrane Database of Systematic Reviews. 2025. https://doi.org/10.1002/14651858.CD012942.pub2
  8. Gosmann NP, Costa MdA, Jaeger MdB, et al. Selective serotonin reuptake inhibitors, and serotonin and norepinephrine reuptake inhibitors for anxiety, obsessive-compulsive, and stress disorders: A 3-level network meta-analysis. PLOS Medicine. 2021. https://doi.org/10.1371/journal.pmed.1003664
  9. U.S. Food and Drug Administration. PRISTIQ (desvenlafaxine) extended-release tablets, prescribing information. 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f43610c-f290-46ea-d186-4f998ed99fce
  10. U.S. Food and Drug Administration. EFFEXOR XR (venlafaxine hydrochloride) extended-release capsules, prescribing information. 2023. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c848a5d8-ba94-4c84-80e3-0bf35fb8e32e
  11. Williams T, Hattingh CJ, Kariuki CM, et al. Pharmacotherapy for social anxiety disorder (SAnD). Cochrane Database of Systematic Reviews. 2017. https://doi.org/10.1002/14651858.CD001206.pub3
  12. Bighelli I, Castellazzi M, Cipriani A, et al. Antidepressants versus placebo for panic disorder in adults. Cochrane Database of Systematic Reviews. 2018. https://doi.org/10.1002/14651858.CD010676.pub2
  13. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database of Systematic Reviews. 2014. https://doi.org/10.1002/14651858.CD007115.pub3
  14. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. The Lancet Neurology. 2015. https://doi.org/10.1016/S1474-4422(14)70251-0
  15. Birkinshaw H, Friedrich CM, Cole P, et al. Antidepressants for pain management in adults with chronic pain: a network meta-analysis. Cochrane Database of Systematic Reviews. 2023. https://doi.org/10.1002/14651858.CD014682.pub2
  16. Welsch P, Üçeyler N, Klose P, et al. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database of Systematic Reviews. 2018. https://doi.org/10.1002/14651858.CD010292.pub2
  17. Ferreira GE, McLachlan AJ, Lin CWC, et al. Efficacy and safety of antidepressants for the treatment of back pain and osteoarthritis: systematic review and meta-analysis. BMJ. 2021. https://doi.org/10.1136/bmj.m4825
  18. U.S. Food and Drug Administration. Duloxetine delayed-release capsules, prescribing information (Lupin Pharmaceuticals). 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=829a4f51-c882-4b64-81f3-abfb03a52ebe
  19. Sun Z, Hao Y, Zhang M. Efficacy and Safety of Desvenlafaxine Treatment for Hot Flashes Associated with Menopause: A Meta-Analysis of Randomized Controlled Trials. Gynecologic and Obstetric Investigation. 2013. https://doi.org/10.1159/000348564
  20. Ramaswami R, Villarreal MD, Pitta DM, et al. Venlafaxine in management of hot flashes in women with breast cancer: a systematic review and meta-analysis. Breast Cancer Research and Treatment. 2015. https://doi.org/10.1007/s10549-015-3465-5
  21. Maund E, Guski LS, Gøtzsche PC. Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical study reports. Canadian Medical Association Journal. 2017. https://doi.org/10.1503/cmaj.151104
  22. Smith EML, Pang H, Cirrincione C, et al. Effect of Duloxetine on Pain, Function, and Quality of Life Among Patients With Chemotherapy-Induced Painful Peripheral Neuropathy. JAMA. 2013. https://doi.org/10.1001/jama.2013.2813
  23. Cipriani A, Zhou X, Del Giovane C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. The Lancet. 2016. https://doi.org/10.1016/S0140-6736(16)30385-3
  24. Hetrick SE, McKenzie JE, Bailey AP, et al. New generation antidepressants for depression in children and adolescents: a network meta-analysis. Cochrane Database of Systematic Reviews. 2021. https://doi.org/10.1002/14651858.CD013674.pub2
  25. Hammad TA, Laughren T, Racoosin J. Suicidality in Pediatric Patients Treated With Antidepressant Drugs. Archives of General Psychiatry. 2006. https://doi.org/10.1001/archpsyc.63.3.332
  26. Stone M, Laughren T, Jones ML, et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ. 2009. https://doi.org/10.1136/bmj.b2880
  27. Zhou S, Li P, Lv X, et al. Adverse effects of 21 antidepressants on sleep during acute-phase treatment in major depressive disorder: a systemic review and dose-effect network meta-analysis. Sleep. 2023. https://doi.org/10.1093/sleep/zsad177
  28. Alberti S, Chiesa A, Andrisano C, et al. Insomnia and Somnolence Associated With Second-Generation Antidepressants During the Treatment of Major Depression: a meta-analysis. Journal of Clinical Psychopharmacology. 2015. https://doi.org/10.1097/JCP.0000000000000329
  29. Henssler J, Schmidt Y, Schmidt U, et al. Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. The Lancet Psychiatry. 2024. https://doi.org/10.1016/S2215-0366(24)00133-0
  30. Kalfas M, Tsapekos D, Butler M, et al. Incidence and Nature of Antidepressant Discontinuation Symptoms: A Systematic Review and Meta-Analysis. JAMA Psychiatry. 2025. https://doi.org/10.1001/jamapsychiatry.2025.1362
  31. Fava GA, Benasi G, Lucente M, et al. Withdrawal Symptoms after Serotonin-Noradrenaline Reuptake Inhibitor Discontinuation: Systematic Review. Psychotherapy and Psychosomatics. 2018. https://doi.org/10.1159/000491524
  32. Thase ME. Effects of Venlafaxine on Blood Pressure: a meta-analysis of original data from 3744 depressed patients. The Journal of Clinical Psychiatry. 1998. https://doi.org/10.4088/jcp.v59n1002
  33. Serretti A, Chiesa A. Treatment-Emergent Sexual Dysfunction Related to Antidepressants: a meta-analysis. Journal of Clinical Psychopharmacology. 2009. https://doi.org/10.1097/JCP.0b013e3181a5233f
  34. Clayton AH, Hwang E, Kornstein SG, et al. Effects of 50 and 100 mg desvenlafaxine versus placebo on sexual function in patients with major depressive disorder: a meta-analysis. International Clinical Psychopharmacology. 2015. https://doi.org/10.1097/yic.0000000000000094
  35. Petimar J, Young JG, Yu H, et al. Medication-Induced Weight Change Across Common Antidepressant Treatments: A Target Trial Emulation Study. Annals of Internal Medicine. 2024. https://doi.org/10.7326/M23-2742
  36. Huybrechts KF, Bateman BT, Pawar A, et al. Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study. BMJ. 2020. https://doi.org/10.1136/bmj.m237
  37. Orlova Y, Rizzoli P, Loder E. Association of Coprescription of Triptan Antimigraine Drugs and Selective Serotonin Reuptake Inhibitor or Selective Norepinephrine Reuptake Inhibitor Antidepressants With Serotonin Syndrome. JAMA Neurology. 2018. https://doi.org/10.1001/jamaneurol.2017.5144
  38. Li Y, Du X, Wu H. The risk of hyponatremia induced by SSRIs and SNRIs antidepressants: a systematic review and meta-analysis. BMC Pharmacology and Toxicology. 2025. https://doi.org/10.1186/s40360-025-00977-1
  39. De Picker L, Van Den Eede F, Dumont G, et al. Antidepressants and the Risk of Hyponatremia: A Class-by-Class Review of Literature. Psychosomatics. 2014. https://doi.org/10.1016/j.psym.2014.01.010
  40. Lassen D, Ennis ZN, Damkier P. First-Trimester Pregnancy Exposure to Venlafaxine or Duloxetine and Risk of Major Congenital Malformations: A Systematic Review. Basic & Clinical Pharmacology & Toxicology. 2016. https://doi.org/10.1111/bcpt.12497
  41. Masarwa R, Bar-Oz B, Gorelik E, et al. Prenatal exposure to selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors and risk for persistent pulmonary hypertension of the newborn: a systematic review, meta-analysis, and network meta-analysis. American Journal of Obstetrics and Gynecology. 2019. https://doi.org/10.1016/j.ajog.2018.08.030

Everything in the library