What antidepressant has the lowest anticholinergic side effects?

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From the Guidelines

Selective serotonin reuptake inhibitors (SSRIs), particularly sertraline (Zoloft), have the lowest anticholinergic side effects among antidepressants. According to the most recent evidence 1, sertraline is considered one of the preferred agents due to its favorable adverse effect profile, which includes minimal anticholinergic activity.

Key Points

  • Sertraline is typically started at 25-50 mg daily and can be titrated up to 200 mg daily as needed.
  • Other SSRIs with minimal anticholinergic activity include escitalopram (Lexapro) and citalopram (Celexa).
  • These medications work by increasing serotonin levels in the brain without significantly affecting acetylcholine receptors, which is why they cause fewer anticholinergic side effects like dry mouth, blurred vision, constipation, urinary retention, and cognitive impairment.
  • In contrast, older antidepressants like tricyclics (especially amitriptyline and imipramine) have strong anticholinergic properties and should be avoided when these side effects are a concern, as noted in previous guidelines 1.

Considerations

  • The choice of antidepressant should be based on the individual patient's needs and medical history.
  • Patients with conditions that might be exacerbated by anticholinergic effects, such as glaucoma, prostatic hypertrophy, or cognitive impairment, may benefit from SSRIs like sertraline.
  • It is essential to monitor patients for side effects and adjust the dosage accordingly, as recommended in geriatric psychopharmacology principles 1.

From the Research

Antidepressants with Low Anticholinergic Side Effects

  • Bupropion is an antidepressant with no appreciable activity on serotonin concentrations in the central nervous system and has been shown to have fewer anticholinergic side effects compared to other antidepressants 2.
  • Mirtazapine has a unique method of action and has been shown to have fewer anticholinergic side effects, but it can cause increased sedation, appetite, and weight gain 2.
  • Vortioxetine and vilazodone are newer antidepressants that have been shown to have fewer anticholinergic side effects, but they can cause nausea, constipation, and vomiting 2.
  • Tricyclic antidepressants (TCAs) have significant anticholinergic side effects, including dry mouth, blurred vision, and constipation, and are generally not recommended as a first-line treatment for depression 3, 4, 5.
  • Selective serotonin reuptake inhibitors (SSRIs) have fewer anticholinergic side effects compared to TCAs, but can still cause gastrointestinal side effects, such as nausea and diarrhea 3, 4, 5.

Comparison of Antidepressants

  • A study comparing sertraline to other antidepressants found that sertraline was generally associated with a higher rate of participants experiencing diarrhea, but had a trend in favour of sertraline over other antidepressive agents both in terms of efficacy and acceptability 4, 5.
  • Another study found that bupropion had higher overall satisfaction ratings and fewer reports of emotional blunting compared to other antidepressants 6.
  • Mirtazapine has been shown to have a faster onset of action and greater efficacy compared to other antidepressants, but can cause increased sedation and weight gain 2.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Other Antidepressants.

Handbook of experimental pharmacology, 2019

Research

Clinical overview of serotonin reuptake inhibitors.

The Journal of clinical psychiatry, 1990

Research

Sertraline versus other antidepressive agents for depression.

The Cochrane database of systematic reviews, 2010

Research

Sertraline versus other antidepressive agents for depression.

The Cochrane database of systematic reviews, 2009

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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