Excess fatality from desipramine and dosage recommendations

Area of Science:

• Pharmacology
• Toxicology
• Clinical Pharmacy

Background:

• Tricyclic antidepressants (TCAs) exhibit varying toxicity profiles.
• Previous reports indicated higher case fatality rates (CFR) for desipramine compared to other TCAs.
• Understanding these differences is crucial for safe prescribing and overdose management.

Purpose of the Study:

• To quantitatively evaluate the case fatality rate (CFR) of desipramine in comparison to amitriptyline, nortriptyline, and imipramine.
• To explore potential pharmacokinetic reasons for observed toxicity differences.
• To propose adjustments to desipramine's dosing and formulation to mitigate its high CFR.

Main Methods:

• Analysis of the American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System (TESS) database.
• Inclusion of data spanning 20 years (1983-2002).
• Statistical comparison of case fatality rates (CFR) between desipramine and other selected TCAs.

Main Results:

• Desipramine demonstrated significantly higher CFRs: 2.25-fold vs. amitriptyline, 2.31-fold vs. nortriptyline, and 2.62-fold vs. imipramine (P < 0.001).
• Desipramine and nortriptyline possess higher distribution volumes and erythrocyte/plasma ratios than their parent compounds, suggesting lower therapeutic plasma levels.
• Unlike nortriptyline, desipramine's dosage and formulation have not been adjusted to reflect these pharmacokinetic properties.

Conclusions:

• Desipramine exhibits a markedly higher CFR than other commonly used TCAs.
• Pharmacokinetic differences, specifically higher distribution volumes, may contribute to desipramine's toxicity.
• Lowering desipramine's dose, therapeutic plasma level, and maximal pill content is suggested to reduce its associated fatality rate.