Cymbalta (Duloxetine) for Major Depressive Disorder
For major depressive disorder, start duloxetine at 30 mg once daily for 1 week, then increase to the target therapeutic dose of 60 mg once daily. 1, 2, 3
Initial Dosing Strategy
The FDA-approved starting approach is 40-60 mg/day, but the most tolerable initiation strategy is 30 mg once daily for the first week before escalating to 60 mg once daily 1, 2, 3. This gradual titration significantly reduces treatment-emergent nausea—the most common adverse effect—while producing only a transient delay in therapeutic effect compared to starting at 60 mg daily 2. The alternative FDA-approved approach of starting at 40 mg/day (given as 20 mg twice daily) is less commonly used in clinical practice 3.
Target Therapeutic Dose
60 mg once daily is the established therapeutic dose for major depressive disorder 1, 3, 4, 5. While 120 mg/day has been shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefits for most patients with MDD 3, 4. The starting dose of 60 mg once daily provides the best balance of efficacy and tolerability 5.
Administration Guidelines
- Take duloxetine with or without food, swallowed whole—never chew, crush, or open the capsule 3
- Administer once daily at any consistent time of day 3
- If a dose is missed, take it as soon as remembered unless it's almost time for the next dose; never double-dose 3
Monitoring and Response Assessment
Begin monitoring within 1-2 weeks of starting treatment 6. The American College of Physicians recommends assessing patient status, therapeutic response, and adverse effects regularly starting within this timeframe 6. Watch closely for increases in suicidal thoughts and behaviors, agitation, irritability, or unusual behavioral changes, as the risk for suicide attempts is greatest during the first 1-2 months of treatment 6.
If there is inadequate response after 6-8 weeks at 60 mg daily, modify treatment 6. The response rate to antidepressant therapy may be as low as 50%, and insufficient evidence exists to prefer one agent over another as second-line therapy 6.
Duration of Treatment
Continue treatment for 4-9 months after achieving satisfactory response in first-episode depression 6. For patients who have had 2 or more depressive episodes, longer duration therapy (years to lifelong) may be beneficial 6. This continuation phase prevents relapse, which is defined as loss of response during ongoing treatment 6.
Dose Escalation (If Needed)
If considering escalation beyond 60 mg daily due to inadequate response:
- Increase in 30 mg increments, allowing at least 1-2 weeks at each dose level 7
- Maximum dose is 120 mg/day 7, 3
- Rapid dose escalation (60→90→120 mg/day weekly) is safe and tolerable, with most adverse events occurring during the first week at 60 mg rather than during subsequent escalations 8
Discontinuation Protocol
When discontinuing after more than 3 weeks of treatment, taper gradually over at least 2-4 weeks 1, 2. For patients with a history of withdrawal symptoms, consider a slower taper over 3-4 weeks with smaller dose decrements (e.g., 120→100→80→60 mg) 2. Common discontinuation-emergent adverse events include nausea and dizziness 9.
Common Adverse Effects
The most frequently reported adverse events are nausea, dry mouth, headache, constipation, dizziness, fatigue, decreased appetite, and somnolence 7, 9, 4, 10. These are typically mild to moderate in severity and most prominent during the first week of treatment 9, 8. Nausea is the most common reason for treatment discontinuation 9.
Special Populations and Contraindications
- Avoid in patients with creatinine clearance <30 mL/min 2
- Dose reduction required in hepatic disease 2
- In geriatric patients, start at 30 mg once daily for 2 weeks before increasing to 60 mg/day 3
- Duloxetine can cause modest increases in blood pressure and heart rate, requiring monitoring 2, 8
- Routine liver enzyme monitoring is generally unnecessary 1
Clinical Pearls
Duloxetine does not require a DEA number for prescribing—it is not a controlled substance 7. Unlike opioids, it has no significant abuse liability 7. The medication is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) that also demonstrates efficacy for painful physical symptoms that frequently accompany depression 4, 10.