What are some common side effects of selective serotonin reuptake inhibitors (SSRIs)?

[NOTE: This article has been posted prior to peer review for use in an active research program. This content will be updated with a peer reviewed version as soon as it is available.]

Selective serotonin reuptake inhibitors (SSRIs) are generally well tolerated. The incidence of common and very common adverse events with placebo incidence subtracted is listed below.

Table 2: Common and very common adverse effects and the percentage of their incidence less placebo in manufacturers’ drug trials for SSRIs^1-7

Manufacturers note that sexual dysfunction is most likely under-estimated due to the discomfort associated with discussion of these adverse effects.^1-7

A population-based cross-sectional study from 2009 examining the incidence of side effects from SSRIs (n=700) found that sexual dysfunction was present in 56% of participants.⁸ Other common side effects reported included drowsiness (53%), weight gain (49%), dry mouth (19%), insomnia (16%), fatigue (14%), nausea (14%), dizziness (13%), and tremors (12%).

A 2004 meta-analysis of 11 studies (n=1,091) compared the side effect profiles of SSRIs (including paroxetine, fluoxetine, citalopram, fluvoxamine, and sertraline) and tricyclic antidepressants (TCAs; including doxepin, amitriptyline, imipramine, clomipramine, dothiepin, nortriptyline, trimipramine, desipramine, and nomifensine) in an older population with a diagnosis of depression.⁹ SSRIs were overall better tolerated than TCAs, with 22.9% of patients withdrawing treatment due to side effects for TCAs compared to 17.3% for SSRIs. Side effects that occurred with less frequency for those taking SSRIs included dry mouth (7% vs 28% for TCAs), constipation (4.5% vs 7.4%), diarrhea (1.3% vs 3.0%), anorexia (1.6% vs 2.7%), drowsiness (6.5% vs 15.3%), dizziness (7.8% vs 12.2%), lethargy (1.0% vs 4.4%), tremor (1.6% vs 3.0%), and sweating (1.0% vs 1.7%). Side effects that occurred with more frequency for those taking SSRIs included nausea/vomiting (17% vs 7.5%) and sleep disturbance (6% vs 4%).

A 2019 meta-analysis of 21 studies (n=6,331) examined the side effects of SSRIs and benzodiazepines in patients with panic disorder.¹⁰ Compared to placebo, SSRIs increased the incidence of abnormal ejaculation (10.9% vs 0.4%), insomnia (15.6% vs 11.0%), diarrhea (16.4% vs 7.4%), sweating (16.8% vs 10.0%), fatigue (14.0% vs 9.8%), drowsiness (16.2% vs 7.8%), and nausea (27.9% vs 18.8%).

Dose Dependency

Most adverse reactions are dose-dependent in nature. Manufacturer trials for escitalopram and paroxetine found that the following adverse events increased with dose:

Table 3: Incidence of common adverse reactions with increased dose of escitalopram.²

Table 4: Incidence of common adverse reactions with increased dose of paroxetine.⁶

Discontinuation

There are adverse reactions associated with the discontinuation of SSRIs, particularly abrupt discontinuation, including nausea, sweating, mood swings, irritability, agitation, dizziness, paresthesia, tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.^1-7 Clinical practice guidelines recommend that when discontinuing an SSRI, patients gradually reduce their dose if possible to avoid adverse effects.¹¹

A 1995 randomized control trial examined the effects of discontinuation of paroxetine after 12 weeks of use.¹² At two weeks after abrupt discontinuation, 19 of the 55 patients (34.5%) on paroxetine reported adverse effects associated with discontinuation compared to seven of 52 placebo patients (13.5%). The most commonly reported adverse effect was dizziness (7.3% for paroxetine vs 1.9% for placebo).

A 1998 randomized control trial studied adverse events associated with abrupt discontinuation of fluoxetine after 12 weeks of use (n=395).¹³ At six weeks, the only new or worsened adverse events significantly associated with medication discontinuation were dizziness (5.2% vs 0.8% for controls, p=0.048) and rhinitis (10.3% vs 2.8%, p=0.020). The authors noted that patients rated the severity of symptoms mild to moderate, and the adverse events reported were of little clinical significance.

References

1. Celexa [package insert]. Chicago, IL: AbbVie Inc.; 2023.
2. Lexapro [package insert]. Chicago, IL: AbbVie Inc.; 2023.
3. Prozac [package insert]. Indianapolis, IN: Lilly USA; 2023.
4. Fluvocamine Maleate [package insert]. Baudette, MN: ANI Pharmaceuticals; 2023.
5. Paxil CR [package insert]. Weston, FL: Apotex Corp; 2023.
6. Paxil [package insert]. Weston, FL: Apotex Corp; 2024.
7. Zoloft [package insert]. Morgantown, WV: Viatris Specialty; 2023.
8. Cascade E, Kalali AH, Kennedy SH. Real-World Data on SSRI Antidepressant Side Effects. Psychiatry (Edgmont). Feb 2009;6(2):16-8.
9. Wilson K, Mottram P. A comparison of side effects of selective serotonin reuptake inhibitors and tricyclic antidepressants in older depressed patients: a meta-analysis. Int J Geriatr Psychiatry. Aug 2004;19(8):754-62. doi:10.1002/gps.1156
10. Quagliato LA, Cosci F, Shader RI, et al. Selective serotonin reuptake inhibitors and benzodiazepines in panic disorder: A meta-analysis of common side effects in acute treatment. J Psychopharmacol. Nov 2019;33(11):1340-1351. doi:10.1177/0269881119859372
11. Gelenberg A, Freeman M, Markowitz J, et al. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Ed ed: American Psychiatric Association; 2010.
12. Oehrberg S, Christiansen PE, Behnke K, et al. Paroxetine in the treatment of panic disorder. A randomised, double-blind, placebo-controlled study. Br J Psychiatry. Sep 1995;167(3):374-9. doi:10.1192/bjp.167.3.374
13. Zajecka J, Fawcett J, Amsterdam J, et al. Safety of abrupt discontinuation of fluoxetine: a randomized, placebo-controlled study. J Clin Psychopharmacol. Jun 1998;18(3):193-7. doi:10.1097/00004714-199806000-00003