Doxepin Dose Escalation Protocol from 25mg to 150mg
For adults with depression or anxiety requiring therapeutic antidepressant dosing, start at 25mg nightly and increase by 25mg increments every 1-2 weeks, monitoring closely for anticholinergic and sedating side effects, to reach a target of 150mg daily. 1
Critical Context: Two Different Doxepin Uses
The titration strategy depends entirely on the indication:
- Low-dose doxepin (1-6mg) is used exclusively for insomnia via H1-receptor antagonism and requires no titration 1, 2
- Standard-dose doxepin (25-300mg) is used for depression/anxiety as a tricyclic antidepressant and requires gradual titration 1
Since you're starting at 25mg and targeting 150mg, this is clearly for depression or anxiety treatment, not insomnia.
Recommended Titration Schedule
Week 1-2: Start at 25mg nightly (bedtime dosing minimizes daytime sedation) 1
Week 3-4: Increase to 50mg nightly if tolerated 1
Week 5-6: Increase to 75mg nightly 1
Week 7-8: Increase to 100mg nightly 1
Week 9-10: Increase to 125mg nightly 1
Week 11-12: Reach target of 150mg nightly 1
- Each increment should be 25mg increases at 1-2 week intervals to allow assessment of tolerability and therapeutic response 1
- Most patients achieve therapeutic benefit between 75-150mg daily 3
Critical Safety Monitoring
Anticholinergic effects are dose-dependent and include dry mouth, constipation, urinary retention, blurred vision, and confusion (especially problematic in elderly patients) 1
Cardiac monitoring: Doxepin can prolong QRS interval; baseline and follow-up ECGs are prudent, particularly at doses >100mg 4
Sedation and cognitive impairment: These are the most common side effects and may necessitate slower titration or dose reduction 1, 2
Drug interactions: Doxepin is metabolized by CYP2D6 and CYP2C19; concurrent use of inhibitors (SSRIs, clobazam, topiramate) can cause toxicity even at standard doses 4
Pharmacogenomic Considerations
CYP2D6 poor or intermediate metabolizers have dramatically elevated doxepin levels (up to 11.5-fold higher) and are at high risk for toxicity even at standard doses 4
- If unexpected severe side effects occur (confusion, ataxia, excessive sedation, seizures), consider genetic testing for CYP2D6 4
- Poor metabolizers may require starting at 10-12.5mg with slower titration and lower maximum doses 4
Therapeutic Drug Monitoring
Therapeutic plasma concentration range for doxepin plus desmethyldoxepin is traditionally cited as 150-250 ng/mL, though evidence supporting this range is weak 3
- Most patients on standard doses (100-150mg) achieve levels of 50-150 ng/mL, which appears clinically effective 3
- Therapeutic drug monitoring is most useful when toxicity is suspected or response is inadequate despite adequate dosing 3
Common Pitfalls to Avoid
Avoid combining with other anticholinergic medications (antihistamines, antipsychotics, other TCAs) as this increases risk of anticholinergic toxicity 1
Do not use with CYP2D6 inhibitors without dose adjustment; this includes fluoxetine, paroxetine, bupropion, and quinidine 4
Avoid in patients with cardiac conduction abnormalities (2nd or 3rd degree AV block, prolonged QT interval) as doxepin can worsen these conditions 1
Never abruptly discontinue after chronic use; taper gradually to avoid withdrawal symptoms 1
When to Stop or Adjust Titration
Hold dose escalation if:
- Excessive sedation interfering with daily function 1
- Anticholinergic side effects become intolerable 1
- QRS prolongation >100ms on ECG 4
- New confusion, ataxia, or neurologic symptoms suggesting toxicity 4
Consider slower titration (25mg every 3-4 weeks) in:
- Elderly patients (>65 years) 5
- Patients with hepatic or renal impairment 1
- Patients on interacting medications 4
- Known CYP2D6 poor metabolizers 4
Alternative Approach if Poorly Tolerated
If side effects prevent reaching 150mg, therapeutic benefit may occur at lower doses (75-100mg) in many patients 3