Duloxetine (Cymbalta)

Class

SNRI (Serotonin-Norepinephrine Reuptake Inhibitor)

Mechanism

Enhances serotonergic and noradrenergic activity in the prefrontal cortex and descending pain pathways by inhibiting serotonin and norepinephrine reuptake.

FDA-Approved Use

Major depressive disorder (MDD), generalized anxiety disorder (GAD), fibromyalgia, diabetic peripheral neuropathic pain, chronic musculoskeletal pain.

Off-Label Use

Stress urinary incontinence, mood and cognitive dysfunction in Lewy body dementia (LBD), neuropathic pain in multiple sclerosis (MS), post-stroke depression (PSD), depression in Parkinson’s disease (PD)

Formulation

Oral delayed-release capsules (20 mg, 30 mg, 60 mg)

Titration

20–30 mg p.o. daily, titrating to 60 mg/day as clinically indicated.

Dose Range

30–60 mg/day

Kinetics

Half-life ~12 hours; metabolized via CYP1A2 and CYP2D6; steady state in ~3 days.

Common AEs

Nausea, headache, dry mouth, dizziness, somnolence or insomnia, constipation, decreased appetite, weight loss, and increased blood pressure.

Serious/Rare AEs

Hepatotoxicity, serotonin syndrome, Stevens-Johnson syndrome, SIADH, hyponatremia, orthostatic hypotension.

Monitoring

Monitor sodium in older adults, blood pressure, liver function tests in those with hepatic risk, and mental status for suicidality.

Black Box Warning

Increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults with MDD.

Considerations

Duloxetine may cause SIADH and hyponatremia, particularly in older adults, warranting slow titration and monitoring. In individuals with MS, duloxetine may reduce neuropathic pain and improve affective symptoms, though fatigue or sedation may occur. It may support mood and cognition in patients with LBD but should be used cautiously due to orthostatic hypotension risk. Avoid use in severe hepatic or renal impairment due to toxicity concerns. Duloxetine may lower the seizure threshold and should be used cautiously in patients with epilepsy or a history of structural brain injury.