At what dose does doxepin (tricyclic antidepressant) prolong the QT (quantum time) interval?

Doxepin QT Interval Prolongation: Dose Considerations

Doxepin does not significantly prolong the QT interval at therapeutic doses up to 6 mg, but may cause QT prolongation at higher doses above 50 mg, with risk increasing in a dose-dependent manner.

Evidence on Doxepin and QT Prolongation

The evidence regarding doxepin's effect on QT interval shows a dose-dependent relationship:

• At lower doses (6 mg), which are used for insomnia treatment, doxepin shows no significant effect on QT interval prolongation 1. A thorough QT study revealed no effects on QTcI (individually corrected QT) with doxepin doses up to 50 mg, suggesting that low-dose doxepin therapy is unlikely to increase QT intervals 1.

• At higher doses used for depression (mean daily dosage of 169 mg), doxepin has been shown to prolong QTc from 417 ± 36 to 439 ± 28 msec (p < 0.03) after 6 weeks of treatment 2.

• Tricyclic antidepressants as a class are known to increase the risk of ventricular arrhythmias, as noted in guidelines for drug interactions 3.

Risk Assessment and Monitoring

When prescribing doxepin, consider the following:

• Dose-related risk: QT prolongation risk increases with higher doses, particularly above 50 mg
• Patient factors: Risk is higher in patients with:
  • Pre-existing cardiac conditions
  • Electrolyte abnormalities (especially hypokalemia)
  • Concomitant use of other QT-prolonging medications
  • Advanced age
  • Female gender

Recommendations for Clinical Practice

1. Baseline ECG: Obtain before starting doxepin at doses above 50 mg

2. Dose considerations:

   • For insomnia (3-6 mg): Minimal risk of QT prolongation
   • For depression (75-300 mg): Monitor for QT prolongation

3. ECG monitoring:

   • Follow Class IIa recommendations: Evaluate QT interval before initiation of treatment and during dose titration when using higher doses 3
   • If QTc reaches >500 ms or increases by >60 ms compared with baseline, treatment should be ceased or dose reduced 3

4. Avoid concomitant use of other QT-prolonging medications when possible, including:

   • Antiarrhythmics (especially class IA and III)
   • Certain antibiotics (macrolides, fluoroquinolones)
   • Antipsychotics
   • Other antidepressants with QT effects
   • Antiemetics (e.g., ondansetron)

Clinical Pitfalls to Avoid

1. Overlooking drug interactions: Concomitant use of multiple QT-prolonging drugs significantly increases risk 3

2. Ignoring electrolyte disturbances: Hypokalemia should be avoided during treatment with drugs capable of prolonging the QT interval 3

3. Relying solely on standard 12-lead ECG: Signal-averaged ECG may be more sensitive for detecting subtle QT changes with doxepin 2

4. Failing to recognize high-risk patients: Patients with heart disease, elderly patients, and those with electrolyte abnormalities require more careful monitoring

In summary, doxepin's effect on QT interval is dose-dependent, with minimal risk at doses used for insomnia (≤6 mg) but increasing risk at higher antidepressant doses (>50 mg), particularly when combined with other risk factors.