What are the serious side effects of serotonin norepinephrine reuptake inhibitors (SNRIs)?

Hypersensitivity

Some patients may exhibit an allergic reaction to serotonin norepinephrine reuptake inhibitors (SNRIs), including rash, hives, angioedema, and anaphylaxis.^1-6 Manufacturers advise that patients with a known history of hypersensitivity to SNRIs or any of their inactive ingredients should avoid the use of SNRIs. Hypersensitivity reactions to SNRIs are rare and have been reported in case reports and post-marketing surveillance, so their exact incidence is unknown. 

Suicidal Ideation

A pooled analyses of placebo-controlled studies in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients showed that treatment can increase the incidence of suicidal thoughts and behaviors in  patients..^1-6 Specifically, among those under 18 years old, there were 14 additional cases per 1,000 patients treated. For those aged 18-24, there were 5 additional cases per 1,000 patients treated.

A meta‑analysis of 372 double‑blind, randomized, placebo‑controlled trials submitted to the U.S. Food and Drug Administration included 99,231 adult patients treated with one of 11 antidepressant agents, including SSRIs and SNRIs.⁷ Across all trials, the overall odds ratio (OR) for suicidal behavior or ideation with antidepressants compared to placebo was 0.85 (95% Confidence interval [CI] [0.71–1.02]; p=0.08), indicating no significant excess risk in the adult population. Age‑stratified analyses revealed a clear gradient. In patients aged 18–24 years, the OR was 1.62 (95% CI [0.97–2.71]; p=0.07), corresponding to an absolute risk difference of +0.55% (95% CI, –0.01% to 1.31%), or 5.5 additional cases per 1,000 patients treated. In adults aged 25–64 years, the OR was 0.79 (95% CI [0.64–0.98]; p=0.03), with an absolute risk difference of –0.19% (95% CI, –0.37% to –0.01%), equivalent to 1.9 fewer cases per 1,000 patients treated. In patients aged ≥65 years, the OR was 0.37 (95% CI [0.18–0.76]; p=0.007), with an absolute risk difference of –0.37% (95% CI, –0.61% to –0.13%), or 3.7 fewer cases per 1,000 patients treated. These findings established that antidepressant‑associated suicidality is age‑dependent, with risk confined to younger adults and a protective effect in older patients. Importantly, the FDA noted that the excess risk in younger adults was concentrated in the first 4–8 weeks of treatment, with majority of events occurring in this early interval. Beyond 16 weeks, data were insufficient to determine whether risk persisted, as most randomized trials were short‑term.⁷

A retrospective cohort of 162,625 patients aged 10–64 years initiating therapy with citalopram, fluoxetine, or sertraline was analyzed to assess the relationship between antidepressant dose, age, and deliberate self‑harm.⁸ Patients were stratified by starting dose: modal versus high dose (defined as ≥40 mg fluoxetine equivalent). Within the first 90 days of treatment, the hazard ratio (HR) for deliberate self‑harm in patients aged 10–24 years initiating high‑dose therapy compared with modal dose was 2.2 (95% CI, 1.6–3.0; p<0.001), corresponding to an absolute risk difference of 11.2 events per 1,000 patients. In patients aged 25–64 years, the HR was 1.2 (95% CI, 0.8–1.9; p=0.33), with an absolute risk difference of 0.0 events per 1,000 patients, confirming no measurable increase in risk in the older cohort. Temporal analyses demonstrated that the excess risk in younger patients was concentrated in the first 30 days of treatment, with declining incidence between days 31–90. By the end of the 3‑month observation window, the risk had returned to baseline levels. Although the primary analyses focused on SSRIs, clinical extrapolation of the early‑interval signal is typically extended to SNRIs due to overlapping pharmacodynamic activation profiles and similar trial durations; direct SNRI‑exclusive absolute risks by week in observational datasets remain under‑reported.

An analysis of a large data set with 142,090 adult patients from a European drug surveillance program (Arzneimittelsicherheit in der Psychiatrie; AMSP) performed in 85 psychiatric hospitals from 1993 until 2008 found that the incidence rate of suicidal adverse drug reactions for SNRIs was 0.034% (95% Confidence Interval [CI] [0.015-0.068], p=0.001), which is comparable to the rate for selective serotonin reuptake inhibitors (SSRIs) at 0.034% (95% CI [0.020-0.054], p=0.001).⁹ These rates were higher than those for noradrenergic and specific serotonergic antidepressants (NaSSAs) at 0.009% (95% CI [0.002-0.027], p = 0.005) and tricyclic antidepressants (TCAs) at 0.002% (95% CI [0.000-0.014], p=0.01).

An update to the previous analysis with 219,635 adult hospitalized patients was published in 2018.¹⁰ This analysis found that in cases when only one antidepressant was assumed to cause the adverse drug reaction (n=71) that SNRIs had an incidence rate of 0.03% (95% CI [0.016-0.05], p=0.05) compared to SSRIs, that had an incidence 0.05% (95% CI [0.034-0.07], p=0.05). Monoamine oxidase inhibitors (MAOIs) had an incidence rate of 0.05% (95% CI [0.005-0.16]), NaSSAs had an incidence rate of 0.01% (95% CI [0.004-0.02]), TCAs had an incidence rate of 0.00% (95% CI [0.000-0.01]) and other antidepressants 0.04% (95% CI [0.014-0.07]).

Medication labels recommend close monitoring of any patients that are prescribed SNRIs, especially for the first few months of drug therapy and at times of dose change. They also recommend that family members and caregivers remain vigilant for these signs and symptoms and consult the patient's physician if they notice any concerning changes.^1-6

Serotonin Syndrome

SNRIs can trigger serotonin syndrome, a potentially life-threatening condition that occurs when serotonin levels are excessively high in the body.^1-6 Signs and symptoms include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The risk is higher when SNRIs are used with other serotonergic drugs (such as triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair serotonin metabolism like MAOIs.^1-6

A retrospective cohort study using Veterans Health Administration records from 2008-2012 and commercially insured patient records from 2010-2013 examined the incidence of serotonin syndrome.¹¹ Among those taking one non-MAOI serotonergic medication (n=6,885,956), there were 8,188 cases of serotonin syndrome, corresponding to an incidence 1.28 per 1,000 person-years, and for those taking two non-MAOI medications (n=1,019,591), there were 2,478 cases, yielding an incidence of 2.43 per 1,000 (Relative Risk [RR] 1.97, CI [1.88-2.06], p<0.001). For those taking an MAOI and serotonergic drug in combination (n=24,645), there were 129 cases, corresponding to an incidence of 5.22 per 1,000 person-years (RR 3.37, CI [2.84-4.01], p<0.001).

A 2023 retrospective cohort study of 1,978 overdoses that included SSRIs and SNRIs found that of the SNRI overdoses (n=590), 96 cases led to serotonin toxicity (16.3%). The probability of serotonin toxicity increased with increased dose (Odds Ratio [OR] 1.01, 95% CI [0.93-1.10]), for SNRIs vs. SSRIs (OR 1.07, 95% CI [0.99-1.15]), and markedly increased with co-ingestion of an MAOI (OR 33.12, 95% CI [7.5-147]). Co-ingestion of an MAOI increased the probability of serotonin toxicity from 12.7% to 83%.¹²

Discontinuation Syndrome

Stopping or reducing the dose of SNRIs suddenly, especially after higher doses and longer treatment, can cause adverse symptoms.^1-6 Reported symptoms include agitation, anorexia, anxiety, agitation, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, irritability, lethargy, nausea, nervousness, nightmares, seizures, sensory disturbances including shock-like electrical sensations, somnolence, sweating, tinnitus, tremor, vertigo, and vomiting.

A 2018 systematic review looked at withdrawal symptoms after discontinuation of Venlafaxine in 61 reports comprised of double-blind randomized controlled trials, open trials, and case reports.¹³ Their calculations showed a significantly higher incidence of discontinuation symptoms with any dosage (52% with 37.5 mg/day, 35% with 75 mg/day, and 78% with 150 mg/day) compared to placebo (~12%).

A 2001 randomized controlled trial of adverse events associated with taking SNRIs performed an analysis of the effects of abrupt discontinuation of venlafaxine ER in 297 participants over one week.¹⁴ The reported symptoms included dizziness (10-15% vs <1% placebo), light-headedness (8-15% vs 4% placebo), tinnitus (2-13% vs <1% placebo), nausea (6-18% vs 3% placebo), vomiting (3-12% vs <1% placebo), and loss of appetite (4-10% vs 3% placebo). Symptoms began 24-72 hours after the last dose and lasted 3-7 days.

Another study from 2010 (n=374) to compare the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) with placebo in reducing relapse rate in patients with major depressive disorder (MDD) found that at the end of double blind period, post therapy withdrawal symptoms were reported by 53% in the desvenlafaxine group compared to 28% in the placebo group.¹⁵

Hyponatremia

In rare cases, SNRIs can cause hyponatremia.^1-6  Symptoms include headache, difficulty concentrating, memory issues, confusion, weakness, and unsteadiness, which can lead to falls. More severe cases may present with hallucinations, fainting, seizures, coma, respiratory arrest, and even death.

A meta-analysis of 39 studies (n=8,175,111) was conducted to evaluate the presence of hyponatremia in patients taking antidepressants.¹⁶ The incidence rate of hyponatremia among SNRI users was 7.44% (74 cases per 1000 treated) compared to 5.59% for SSRIs (56 cases per 1000 treated), and 2.66% for TCA users (27 cases per 1000 treated). SNRIs were significantly more likely to induce hyponatremia than SSRIs (OR 1.292, 95% CI [1.120-1.491], p<0.001) corresponding to an absolute excess risk of 1.85% (19 additional cases per 1,000 patients), while mirtazapine was significantly less likely to do so (OR 0.607, 95% CI [0.385-0.957], p=0.032).

Mania

SNRIs may precipitate mania or hypomania in patients with bipolar disorder being treated for a depressive episode.^1-6 During all major depressive disorder phase 2 and 3 studies of desvenlafaxine, mania was reported in approximately 0.02% of patients in treatment arms.¹ For duloxetine, activation of mania or hypomania were reported in 0.1% (4/3779) of treated patients compared to 0.04% (1/2536) of placebo patients.² For levomilnacipran, incidence rates were the same in treatment and placebo arms (0.2%).³ For venlafaxine, mania or hypomania occurred in 0.5% of treated patients.⁵

A study investigated the risk of switches in mood polarity into hypomania and mania during acute (10-week) and continuation trials (up to 1 year) of antidepressant therapy (bupropion, sertraline, or venlafaxine) in bipolar depressive patients. In patients taking venlafaxine during acute treatment trials (n=86), 11.6% of patients experienced threshold switches to full-duration hypomania, and 9.3% experienced switches to mania. During continuation treatment (n=31), these rates increased to 25.8% for hypomania and 22.6% for mania.¹⁷ By comparison, in the sertraline arm (n=89 acute; n=28 continuation), switch rates were lower: 7.9% hypomania and 6.7% mania in acute trials, and 18.0% hypomania and 14.0% mania in continuation. The bupropion arm (n=89 acute; n=30 continuation) showed the lowest risk: 4.4% hypomania and 3.3% mania in acute trials and 13.3% hypomania and 10.0% mania in continuation.

Bleeding

Manufacturer labels state that SNRIs can raise the risk of bleeding events, including ecchymosis, hematoma, nosebleeds, petechiae, and hemorrhage. The risk is heightened when SNRIs are taken with other medications known to increase bleeding risk, such as aspirin, NSAIDs, antiplatelet drugs, warfarin, and other anticoagulants.^1-6

One analysis of 317,824 elderly patients taking antidepressants between 1992-1998 ranked medications as having high, intermediate, or low levels of serotonin reuptake inhibition based on the magnitude of their effect on serotonin transporter.¹⁸ Venlafaxine was ranked as intermediate. The overall incidence of gastrointestinal bleeding was higher among those in the high serotonin reuptake inhibition group (7.4 events per 1,000 person years for intermediate group vs 6.6 events for low group). Among those also taking NSAIDs, incidence jumped from 5.8 to 16.7 events per 1,000 person years for those in the low group and from 6.2 to 17.4 events for those in the intermediate group. Incidence was similarly higher for those taking anticoagulants (6.3 vs 17.3 in low group, 7.2 vs 14.3 in intermediate group).

Angle-Closure Glaucoma

Patients with anatomically narrow angles in their eyes may be at risk of angle-closure glaucoma when taking SNRIs.^1-6 Antidepressants, including SNRIs, can cause pupillary dilation, which can narrow angles, block fluid drainage in the eyes, and lead to increased eye pressure. Manufacturers advise against using SNRIs in patients with untreated anatomically narrow angles.

Cases of angle-closure glaucoma associated with SNRI use have only been reported in case studies, making the exact incidence difficult to estimate. In clinical trials conducted by manufacturers involving thousands of participants, no cases were reported.^1-6

Interstitial Lung Disease

Venlafaxine has been associated with interstitial lung disease and eosinophilic pneumonia.^5,6 However, cases are so rare that it is difficult to know the exact relationship between SNRIs and lung disease. A 2017 case-control study identified only ten cases of those with interstitial lung disease who had taken an SSRI or SNRI that were not otherwise excluded for other potential confounding factors.¹⁹

Seizures

Patients with seizure disorders were excluded from drug trials, so any effect of SSRIs on these types of pre-existing conditions is relatively unknown.^1-6 Therefore, manufacturers advise using caution when prescribing SSRIs to those with seizure disorders.

A study of 151,005 depressed patients found 619 had seizures. The incidence rates per 10,000 person-years were 15.44 (95% CI [8.99-21.89]) for SNRI users, 12.44 (95% CI [10.67-14.21]) for SSRI users, and 8.33 (95% CI [4.68-11.98]) for TCA users. In a comparison of patients that took venlafaxine in the past (n=3,021) to patients currently taking venlafaxine (n=74), 19.6% reported having seizures in the past-venlafaxine use group compared to 36.5% in the current users’ group. Use of venlafaxine was associated with significantly increased odds of seizures compared with non-use (adjusted OR 2.52, 95% CI [1.44-4.42]).²⁰

References

1. Pristiq (Desvenlafaxine extended-release tablets) [package insert]. New York, NY; Pfizer 2023.
2. Cymbalta (Duloxetine delayed-release capsules) [package insert]. Indianapolis, IN; Eli Lilly 2023.
3. Fetzima (Levomilnacipran extended-release capsules) [package insert]. North Chicago, IL; AbbVie 2024.
4. Savella (Milnacipran hydrochloride tablets) [package insert]. North Chicago, IL; AbbVie 2024.
5. Effexor [package insert]. Philadelphia, PA: Wyeth Pharmeceuticals; 2012.
6. Effexor XR (Venlafaxine extended-release tablets) [package insert]. Portage, MI: Upjohn; 2023.
7. 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. Aug 11 2009;339:b2880. doi:10.1136/bmj.b2880
8. Miller M, Swanson SA, Azrael D, Pate V, Stürmer T. Antidepressant Dose, Age, and the Risk of Deliberate Self-harm. JAMA Internal Medicine. 2014;174(6):899-909. doi:10.1001/jamainternmed.2014.1053
9. Stübner S, Grohmann R, von Stralendorff I, et al. Suicidality as rare adverse event of antidepressant medication: report from the AMSP multicenter drug safety surveillance project. J Clin Psychiatry. Oct 2010;71(10):1293-307. doi:10.4088/JCP.09m05912blu
10. Stübner S, Grohmann R, Greil W, et al. Suicidal Ideation and Suicidal Behavior as Rare Adverse Events of Antidepressant Medication: Current Report from the AMSP Multicenter Drug Safety Surveillance Project. International Journal of Neuropsychopharmacology. 2018;21(9):814-821. doi:10.1093/ijnp/pyy048
11. Nguyen CT, Xie L, Alley S, McCarron RM, Baser O, Wang Z. Epidemiology and Economic Burden of Serotonin Syndrome With Concomitant Use of Serotonergic Agents: A Retrospective Study Utilizing Two Large US Claims Databases. Prim Care Companion CNS Disord. Dec 28 2017;19(6)doi:10.4088/PCC.17m02200
12. Cooper J, Duffull SB, Isbister GK. Predicting serotonin toxicity in serotonin reuptake inhibitor overdose. Clin Toxicol (Phila). Jan 2023;61(1):22-28. doi:10.1080/15563650.2022.2151455
13. Fava Giovanni A, Benasi G, Lucente M, Offidani E, Cosci F, Guidi J. Withdrawal Symptoms after Serotonin-Noradrenaline Reuptake Inhibitor Discontinuation: Systematic Review. Psychotherapy and Psychosomatics. 2018;87(4):195-203. doi:10.1159/000491524
14. Allgulander C, Hackett D, Salinas E. Venlafaxine Extended Release (ER) in the Treatment of Generalised Anxiety Disorder: Twenty-four-week placebo-controlled dose-ranging study. British Journal of Psychiatry. 2001;179(1):15-22. doi:10.1192/bjp.179.1.15
15. Rickels K, Montgomery SA, Tourian KA, et al. Desvenlafaxine for the Prevention of Relapse in Major Depressive Disorder: Results of a Randomized Trial. Journal of Clinical Psychopharmacology. 2010;30(1):18-24. doi:10.1097/JCP.0b013e3181c94c4d
16. Gheysens T, Van Den Eede F, De Picker L. The risk of antidepressant-induced hyponatremia: A meta-analysis of antidepressant classes and compounds. Eur Psychiatry. Feb 26 2024;67(1):e20. doi:10.1192/j.eurpsy.2024.11
17. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. Feb 2006;163(2):232-9. doi:10.1176/appi.ajp.163.2.232
18. van Walraven C, Mamdani MM, Wells PS, Williams JI. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ (Clinical research ed). Sep 22 2001;323(7314):655-8. doi:10.1136/bmj.323.7314.655
19. Rosenberg T, Lattimer R, Montgomery P, Wiens C, Levy L. The relationship of SSRI and SNRI usage with interstitial lung disease and bronchiectasis in an elderly population: a case-control study. Clin Interv Aging. 2017;12:1977-1984. doi:10.2147/cia.S144263
20. Bloechliger M, Ceschi A, Rüegg S, et al. Risk of Seizures Associated with Antidepressant Use in Patients with Depressive Disorder: Follow-up Study with a Nested Case–Control Analysis Using the Clinical Practice Research Datalink. Drug Safety. 2016/04/01 2016;39(4):307-321. doi:10.1007/s40264-015-0363-z