What are some common side effects of serotonin norepinephrine reuptake inhibitors (SNRIs)?

Serotonin norepinephrine reuptake inhibitors (SNRIs) can have a range of side effects based on the dosage or formulation of the medication. The table below summarizes the incidence of common and very common adverse events with placebo incidence subtracted.^1-6

Table 1: Common and very common adverse effects and the percentage of their incidence less placebo in manufacturers’ drug trials for SNRIs^1-4,6

Sexual side effects

Manufacturers note that sexual dysfunction is most likely under-estimated due to the discomfort associated with discussion of these adverse effects.^1-6

A multicenter cross-sectional study (6,297) found the prevalence of sexual dysfunction among patients taking venlafaxine XR was 36-43%. The odds ratio of sexual dysfunction in venlafaxine XR users was 2.36 (95% CI [1.80-3.09]).⁷ In a multicenter, prospective, open-label study carried out by the Spanish working group for the study of psychotropic-related sexual dysfunction, the incidence rate of sexual dysfunction in patients taking venlafaxine was 67.3%.⁸

An 8‑week randomized controlled trial, compared duloxetine, escitalopram, and placebo in patients with major depressive disorder who had no baseline sexual dysfunction.⁹ Using the changes in sexual functioning questionnaire (CSFQ), they found that 33.3% of patients on duloxetine and 48.7% on escitalopram developed treatment‑emergent sexual dysfunction, compared with 16.7% on placebo. These effects were evident by the end of the 8‑week treatment period, with escitalopram showing the highest risk across desire, arousal, and orgasm domains, while duloxetine carried a lower but still significant risk relative to placebo.

A 8‑week prospective naturalistic study of 72 patients with major depressive disorder, found that 44.6% of patients treated with desvenlafaxine developed sexual dysfunction, most commonly decreased desire (35%), orgasmic dysfunction (28%), and arousal difficulties (22%).¹⁰ These rates were lower than those typically reported for SSRIs (55–70%) but still significantly higher than placebo (15–20%), confirming that desvenlafaxine, like other SNRIs, carries a substantial though somewhat reduced risk of sexual side effects compared to SSRIs.

Elevated Blood Pressure

SNRIs have been shown to increase blood pressure and even precipitate hypertension.^1-6 The incidence of increased blood pressure in manufacturer drug trials ranged from 0-2% and hypertension ranged from 2-5%. The extent to which SNRIs increase blood pressure is dependent on the formulation and dose.

Short-term pre-marketing studies of desvenlafaxine demonstrated a dose-dependent relationship in blood pressure increase, with those taking 50 mg experiencing a mean increase of 1.2/0.7 mmHg, 100 mg 2.0/0.8 mmHg, 200 mg 2.5/1.8 mmHg, and 400 mg 2.1/2.3 mmHg compared to -1.4/-0.6 for placebo.¹ Similarly, those taking higher doses were more likely to have sustained hypertension (0.5% placebo, 1.3% 50 mg, 0.7% 100 mg, 1.1% 200 mg, 2.3% 400 mg).

Duloxetine treatment was associated with mean increases of 0.5/0.8 mmHg compared to mean decreases of 0.6/0.3 mmHg in placebo-treated patients.² There was no significant difference in the frequency of sustained hypertension.

In manufacturer trials for levomilnacipran, the mean change in blood pressure from baseline to end of treatment was 3.0/3.2 mmHg for those in the intervention arm compared to -0.4/0.0 mmHg for the placebo arm.³ The threshold for hypertension was reached for 0.4% more intervention patients than placebo (1.8% vs 1.2%), and 3.3% more intervention patients experienced an upward shift in hypertensive status defined as normal/pre-hypertensive to stage I or stage II hypertension (10.4% vs 7.1%).

A double-blind, placebo-controlled ambulatory blood pressure monitoring study evaluated the effects of up to 200 mg/day of milnacipran on blood pressure in 321 fibromyalgia patients.⁴ Among those who were normotensive at baseline, a higher proportion of milnacipran-treated patients had a hypertensive blood pressure measurement at week four (17.7%, n=21/119) and week seven (14.3%, n=15/105) compared to placebo-treated patients (3.7%, n=2/54 and 0%, 0/49, respectively).

Across clinical studies of venlafaxine ER, 1.4% of treated patients experienced a ≥15 mmHg increase in supine diastolic blood pressure with an absolute DBP ≥105 mmHg, compared to 0.9% of patients on placebo.⁶ Similarly, 1.0% of venlafaxine ER–treated patients experienced a ≥20 mmHg increase in supine systolic blood pressure with an absolute SBP ≥180 mmHg, compared to 0.3% of placebo patients. Treatment with venlafaxine ER was also associated with sustained hypertension, with incidence rates of 3% in major depressive disorder, 0.5% in generalized anxiety disorder, 0.6% in social anxiety disorder, and 0.9% in panic disorder.

Discontinuation

In clinical trials conducted by manufacturers, the following percentages of patients discontinued therapy for clinical adverse experiences. Placebo results are noted where the information was available.

• Desvenlafaxine XR: 12% (3% placebo)¹
• Duloxetine:²
  • MDD: 8.4% (4.6% placebo)
  • GAD: 13.7% (5% placebo)
  • DPNP: 12.9% (5.1% placebo)
  • Fibromyalgia: 17.5% (10.1%)
  • Chronic pain due to osteoarthritis: 15.7% (7.3% placebo)
  • Chronic low back pain: 16.5% (6.3% placebo)
• Levomilnacipran: 9% (3% placebo)³
• Milnacipran:⁴
  • 100mg/day dose: 23%
  • 200mg/day dose: 26%
• Venlafaxine: 19%⁵
• Venlafaxine XR : 12% (4% placebo)⁶

There are adverse reactions associated with the discontinuation of SNRIs, particularly abrupt discontinuation, including 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.^1-6

Manufacturers recommend that when discontinuing an SNRI, patients gradually reduce their dose if possible to avoid adverse effects.^1-4,6

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. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. Apr 2002;63(4):357-66. doi:10.4088/jcp.v63n0414
8. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry. 2001;62 Suppl 3:10-21.
9. Clayton A, Kornstein S, Prakash A, Mallinckrodt C, Wohlreich M. Changes in Sexual Functioning Associated with Duloxetine, Escitalopram, and Placebo in the Treatment of Patients with Major Depressive Disorder. The Journal of Sexual Medicine. 2007;4(4_Part_1):917-929. doi:10.1111/j.1743-6109.2007.00520.x
10. Montejo AL, Becker J, Bueno G, et al. Frequency of Sexual Dysfunction in Patients Treated with Desvenlafaxine: A Prospective Naturalistic Study. J Clin Med. May 21 2019;8(5)doi:10.3390/jcm8050719