Can a patient with a history of depression and severe dry mouth, currently taking duloxetine (Cymbalta), take 60 mg every other day?

Duloxetine Every-Other-Day Dosing Is Not Recommended

Taking duloxetine 60 mg every other day is not an appropriate dosing strategy and should be avoided. The FDA-approved dosing for duloxetine specifies daily administration, and there is no evidence supporting alternate-day dosing for any indication 1.

Why Every-Other-Day Dosing Is Problematic

Pharmacokinetic Considerations

• Duloxetine has a half-life of approximately 12 hours, meaning that every-other-day dosing would result in significant fluctuations in drug levels, potentially leading to both loss of therapeutic efficacy and increased risk of discontinuation symptoms 1.
• The FDA label explicitly states that if a dose is missed, patients should take it as soon as remembered, but should not take two doses at the same time—this underscores the importance of consistent daily dosing 1.

Approved Dosing Regimens

• For depression: The recommended starting dose is 40-60 mg/day (given as 20 mg twice daily or 60 mg once daily), with some patients starting at 30 mg once daily for 1 week before increasing to 60 mg once daily 1.
• For diabetic peripheral neuropathic pain: The approved dose is 60 mg once daily, with no evidence that higher doses provide additional benefit 2, 1.
• Multiple clinical trials have established efficacy at 60 mg once daily or 40 mg/day (20 mg twice daily), with consistent daily administration 3, 4, 5.

Addressing Tolerability Concerns

If Dry Mouth Is the Primary Issue

Since this patient has severe dry mouth, the following management strategies should be implemented while maintaining daily duloxetine dosing:

• Conservative measures first: Optimize hydration by increasing water intake throughout the day, use saliva substitutes (moisture-preserving mouth rinses or sprays), and employ salivary stimulants like sugar-free chewing gum or lozenges containing xylitol 6.
• Dry mouth is a known side effect: Duloxetine commonly causes dry mouth, along with nausea, somnolence, dizziness, and constipation, but these effects tend to be mild to moderate and transient 2.
• For severe cases: Consider systemic sialagogues such as pilocarpine 5 mg orally three to four times daily if conservative measures fail 2, 6.
• Dental referral: Ensure adequate oral hygiene and protect against dental caries risk, which increases with chronic xerostomia 6.

If Dose Reduction Is Needed

Rather than every-other-day dosing, consider these evidence-based alternatives:

• Lower daily dose: The FDA label indicates that for patients with tolerability concerns, a lower starting dose of 30 mg once daily may be appropriate, with gradual titration to 60 mg once daily 1.
• Divided dosing: Some studies used 20 mg twice daily (40 mg/day total) with demonstrated efficacy, though the 60 mg once daily dose showed more consistent effectiveness 4.
• Gradual discontinuation if needed: If discontinuation is being considered, duloxetine should be tapered gradually rather than stopped abruptly to minimize discontinuation symptoms 1.

Clinical Efficacy Data Supporting Daily Dosing

• Duloxetine 60 mg once daily demonstrated superiority over placebo in reducing depression symptoms with effect sizes of 0.12 to 0.72 for response rate and numbers needed to treat (NNT) of 3-16 5.
• For diabetic neuropathic pain, the NNT to achieve at least 50% pain reduction was 5.2 for 60 mg/day 2.
• Long-term studies (up to 52 weeks) demonstrated sustained efficacy with daily dosing, with estimated remission probabilities of 50.8% at 6 weeks, 75.6% at 28 weeks, and 81.8% at 52 weeks 7.

Important Caveats

• Depression management: Given this patient's history of depression, maintaining therapeutic drug levels is critical for preventing relapse, which makes consistent daily dosing essential 1, 5.
• Discontinuation syndrome risk: Irregular dosing patterns increase the risk of discontinuation symptoms including dizziness, which occurred in 8.3% of patients after stopping duloxetine 7.
• No evidence for alternate-day dosing: There are no published studies or guidelines supporting every-other-day administration of duloxetine for any indication 1, 3, 4, 5.