Chronic imipramine therapy can lead to fatal accumulation of its active metabolite desipramine, particularly in patients with impaired CYP2D6 metabolism or those on concurrent phenothiazine therapy.
Answers are grounded in this paper and cite their sources.
May warrant metabolite monitoring in chronic TCA therapy; leaves open whether CYP2D6-guided dosing prevents fatalities.
In two unrelated cases, a 7-year-old boy and a 21-year-old woman died suddenly while receiving chronic imipramine therapy. In the boy, concentrations of imipramine were: Left femoral blood 0.5 mg/L, right femoral blood 1.2 mg/L, aorta blood 1.0 mg/L, liver 68 mg/Kg, and for the active metabolite, desipramine, left femoral blood 6.7 mg/L, right femoral blood 9.9 mg/L, aorta blood 8.7 mg/L, liver 400 mg/Kg. In the woman, the imipramine concentrations were: Femoral blood 0.6 mg/L, liver 37 mg/Kg, and of the active metabolite, desipramine, femoral blood 3.74 mg/L, liver 261 mg/Kg. In both cases, the scene investigation strongly indicated that neither individual had ingested an acute overdose. The very high ratios of desmethyl metabolite to parent drug are consistent with this observation. Impaired metabolism due to a genetically determined "slow metabolizer" phenotype of cytochrome CYP2D6, and/or concurrent therapy with phenothiazines, is suggested as a possible mechanism for the apparent fatal accumulation of these tricyclic antidepressants.
No takes yet. Share an insight, caveat, or question.
Swanson et al. (1997) studied this question.
Synapse has enriched 5 related papers. Consider them for comparative context: