Which antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), can cause diarrhea or loose stools?

Antidepressants That Cause Loose Stools/Diarrhea

Sertraline has the highest rate of diarrhea among all second-generation antidepressants, while SSRIs as a class commonly cause diarrhea through their effects on serotonin-mediated gut motility. 1

SSRIs: Primary Culprits for Diarrhea

Sertraline (Zoloft) - Highest Risk

• Sertraline causes diarrhea/loose stools significantly more than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, or venlafaxine. 1
• FDA labeling data shows diarrhea/loose stools occur in 18-21% of sertraline-treated patients across multiple indications (major depression, OCD, panic disorder, social anxiety disorder) compared to 8-10% with placebo. 2
• Sertraline has the highest probability of digestive side effects among SSRIs, with a probability ranking of 0.611. 3
• Diarrhea is one of the most common reasons for sertraline discontinuation, occurring in 2% of patients (twice the placebo rate). 2

Other SSRIs with Diarrhea Risk

• Escitalopram and sertraline are the least tolerated antidepressants on the gastrointestinal tract, being associated with diarrhea among other GI side effects. 4
• Paroxetine reduces orocaecal transit time (accelerates gut motility), which can contribute to loose stools, though it has lower diarrhea rates than sertraline. 5
• Fluoxetine has the lowest probability of digestive side effects among SSRIs (ranking 0.548), making it a better choice if diarrhea is a concern. 3
• Citalopram, fluvoxamine, and paroxetine all cause diarrhea but at lower rates than sertraline. 1

SNRIs: Moderate Diarrhea Risk

• SNRIs (duloxetine and venlafaxine) have slightly higher discontinuation rates due to adverse effects compared to SSRIs as a class, with nausea and vomiting being more prominent than diarrhea. 1
• Duloxetine and venlafaxine show 67% and 40% higher discontinuation risks compared to SSRIs, primarily due to nausea rather than diarrhea. 1
• Venlafaxine does not significantly affect colonic transit in the same way SSRIs do. 6

Mechanism: Why SSRIs Cause Diarrhea

• SSRIs increase serotonin availability in the gut by blocking presynaptic reuptake, which increases gastric and intestinal motility and accelerates transit time. 1
• Approximately 95% of the body's serotonin is in the gastrointestinal tract, where it regulates motility and secretion. 1
• SSRIs accelerate small bowel transit but have variable effects on colonic transit depending on the specific agent. 5, 6

Antidepressants with LOWER Diarrhea Risk

Best Alternatives When Avoiding Diarrhea

• Mirtazapine has the fewest gastrointestinal side effects among antidepressants, being associated only with increased appetite rather than diarrhea. 4
• Bupropion has minimal serotonergic effects and therefore lower risk of diarrhea compared to SSRIs. 1, 7
• Tricyclic antidepressants (TCAs) like amitriptyline actually slow gut transit and reduce diarrhea through anticholinergic effects, making them useful in diarrhea-predominant IBS. 1

Clinical Considerations

Common GI Side Effects Across All Second-Generation Antidepressants

• Diarrhea, constipation, nausea, and abdominal pain are among the most commonly reported adverse events for all second-generation antidepressants. 1
• About 63% of patients receiving second-generation antidepressants experience at least one adverse effect during treatment. 1
• Nausea and vomiting (not diarrhea) are the most common reasons for overall discontinuation in efficacy studies. 1

Serotonin Syndrome Warning

• Combining SSRIs with other serotonergic medications can cause serotonin syndrome, where diarrhea is a cardinal feature along with tremor, delirium, rigidity, and hyperthermia. 1, 7
• Serotonin syndrome occurs in 14-16% of SSRI overdoses. 1

Special Population: IBS Patients

• SSRIs may worsen symptoms in diarrhea-predominant IBS patients due to accelerated transit times. 5
• TCAs are preferred over SSRIs for diarrhea-predominant IBS because they slow gut motility. 1
• The therapeutic effects of antidepressants in IBS appear independent of their effects on depression and may relate to their gut motility effects. 8, 6