duloxetine

General Information

Duloxetine (Cymbalta®) is a serotonin-norepinephrine reuptake inhibitor approved for major depressive disorder, generalized anxiety disorder, diabetic neuropathic pain, fibromyalgia, and chronic musculoskeletal pain.

Duloxetine hydrochloride (duloxetine HCl) is the active ingredient in Cymbalta® and generic delayed-release capsule formulations.

It is often preferred when depressive or anxiety symptoms coexist with neuropathic or somatic pain. Enteric-coated capsules (20, 30, 40, 60 mg) permit once-daily dosing; higher doses can be divided for tolerability.

The compare view and duloxetine evidence feed can support discussions of analgesic benefits, blood-pressure considerations, and augmentation plans; mania-prevention planning can be coordinated via the bipolar disorder hub.

Moderate CYP2D6 inhibition makes interaction checks important (TCAs, antipsychotics, tamoxifen). Because of hepatotoxicity risk, it is generally avoided in substantial hepatic impairment or chronic heavy alcohol use. Coordination with the bipolar disorder hub can support mania-prevention planning in bipolar-spectrum disorders.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Inhibits serotonin (SERT) and norepinephrine (NET) transporters with a ~10:1 affinity ratio; norepinephrine reuptake becomes clinically significant at ≥60 mg/day.

Minimal direct antagonism at muscarinic, histamine, or adrenergic receptors; weak dopamine reuptake inhibition is clinically negligible.

• SERT and NET inhibitor with minimal off-target receptor binding.

Metabolism and Pharmacokinetics

• Enteric-coated pellets dissolve in the intestine; Tmax ~6 hours; elimination half-life ~12 hours (steady state in ~3 days).
• Extensively metabolized in the liver via CYP1A2 and CYP2D6 to inactive metabolites, eliminated in urine (~70%) and feces (~20%).
• Exposure increases in moderate hepatic impairment and severe renal impairment (CrCl <30 mL/min); both are relative contraindications.

Dosing and Administration

• Major depressive disorder (clinical depression) and generalized anxiety disorder: typical initiation is 30 mg once daily for one week for tolerability, then 60 mg once daily. If needed, 90–120 mg/day is sometimes used (divide when >60 mg/day), though antidepressant benefit often plateaus beyond 60 mg/day.
• Maximum recommended dose: 120 mg/day.
• Generally avoided in severe renal impairment (CrCl <30 mL/min) and in substantial hepatic impairment or heavy alcohol use.
• Discontinuation symptoms can occur with abrupt stopping; gradual tapering over ≥2 weeks is common.

Monitoring & Labs

• Blood pressure and heart rate at baseline and periodically, especially during titration and at higher doses.
• Liver-injury symptoms (jaundice, dark urine, abdominal pain, pruritus), particularly in patients with alcohol use disorder or hepatic disease; LFTs are obtained when clinically indicated.
• Sodium in older adults or diuretic users if symptoms suggest hyponatremia (confusion, fatigue, falls).
• Medication reconciliation for serotonergic combinations and for CYP2D6 substrates (TCAs, antipsychotics, beta-blockers, tamoxifen).

Duloxetine is often chosen for combined mood and pain symptoms; track both (functioning and pain interference) to guide dose decisions.

Adverse Effects

Interactions

• Contraindicated with MAOIs, linezolid, or IV methylene blue because of serotonin syndrome; appropriate washouts are required.
• CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) markedly increase duloxetine exposure—combinations are generally avoided or alternatives selected.
• Duloxetine is a moderate CYP2D6 inhibitor—dose adjustments and clinical monitoring may be needed for TCAs, antipsychotics, beta-blockers, and tamoxifen.
• Serotonergic agents (SSRIs, SNRIs, triptans, tramadol, St. John’s wort) increase serotonin syndrome risk; counseling often covers symptom recognition and when to seek care.
• Additive bleeding risk with NSAIDs, antiplatelets, and anticoagulants; gastroprotection is sometimes considered.

Other Useful Information

• Counseling often covers signs of liver injury and when to seek care for sustained hypertension, jaundice, or abdominal pain.
• Weight, blood pressure, and (when relevant) glycemic control are commonly tracked over time.
• Smoking (CYP1A2 induction) may modestly decrease levels; clinical impact varies.

References

1. Cymbalta (duloxetine) prescribing information — DailyMed (2025)
2. APA Clinical Practice Guideline for the Treatment of Depression — American Psychiatric Association (2023)Guidelinedepressionclinical
3. CANMAT 2024 Clinical Guidelines for Major Depressive Disorder — Canadian Journal of Psychiatry (2024)
4. Duloxetine for chronic pain and depression: an evidence review — Pain Medicine (2022)
5. Wernicke2008 Duloxetine Hepatic