Imipramine-induced hyperpigmentation: Four cases and a review of the literature

Background: Hyperpigmentation is a side effect of several medications, including amiodarone, bleomycin, chlorpromazine, and minocycline. Objective: The purpose of this study is to describe the clinical and light microscopic findings in 4 patients with imipramine-induced hyperpigmentation and to better understand its origin. Methods: All 4 patients underwent a skin biopsy for light microscopy. In 1 patient, a biopsy specimen was obtained for electron microscopy. Tissue from patient 1 was analyzed with a mass spectrophotometer, and energy-dispersive x-ray analysis was performed on tissue from patients 1 and 2. Results: All 4 women had been taking imipramine for at least 2 years. Hyperpigmentation occurred in a photodistribution on the face, arms, and backs of the hands. Light microscopy in all cases demonstrated golden-brown granules in the superficial dermis, which were strongly positive for Fontana-Masson stain. Electron microscopy demonstrated areas of electron-dense inclusion bodies within macrophages, which were distinct from melanosomes. Mass spectrophotometric and energy-dispersive x-ray analysis of the electron-dense bodies showed the presence of sulfur atoms, and no peak corresponding to that expected for imipramine was found. A peak closely corresponding to phaeomelanin, a sulfur-containing compound, was found. Conclusion: Hyperpigmentation is a side effect of long-term imipramine use. It may result from the deposition of melanin in an unusual form. The melanin pigment is possibly complexed with a metabolite of imipramine, and does not represent the deposition of imipramine in its native form. (J Am Acad Dermatol 1999;40:159-66.)