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Imipramine-induced hyperpigmentation of the skin

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Imipramine-induced hyperpigmentation of the skin
Neda Mehr MD, Jashin J Wu MD, Senait W Dyson MD, Douglas M Woseth MD
Dermatology Online Journal 13 (4): 8

Department of Dermatology, University of California, Irvine, Irvine, CA, USA

A number of drugs are known to induce blue or slate-grey hyperpigmentation of the skin, including amiodarone, tetracyclines, psychotropics, diltiazem, antimalarials, and heavy metals [1, 2, 3, 4, 5, 6]. Imipramine, a tricyclic antidepressant, has also been reported to induce hyperpigmentation; however, there are only twelve reported cases of imipramine-induced hyperpigmentation in the literature to date [7-15].

Clinical synopsis

A 63-year-old-white female presented with slate-grey pigmentation of the face and dorsal hands that had progressively worsened over the previous 3 years. Our patient reported imipramine use of 200mg/d for 30 years for depression.

Physical examination revealed bluish-grey periorbital pigmentation with a general blue-grey hyperpigmentation in a photodistribution of the face (Fig. 1) and dorsal aspects of the hands. A 4-mm punch biopsy taken from left pre-auricular cheek revealed golden-brown granules in the upper and mid dermis (Fig. 2). A Fontana-Masson stain for melanin was positive and a Pearl's stain for iron was negative.

Figure 1Figure 2
Figure 1. Photodistribution of blue-grey pigmentation of the face
Figure 2. Histopathology shows golden-brown pigment in the upper and mid dermis (H&E x 40).


Our histology findings are consistent with those reported in previous cases [7, 8, 9, 10]. Although imipramine-induced hyperpigmentation has been described, the exact mechanism of hyperpigmentation still remains unknown. Ming et al. proposed that the granules of imipramine-induced hyperpigmentation contain phaeomelanin, a sulfur-containing compound; sulfur was observed in the granules on mass spectrophotometry. Because imipramine itself was not discovered in the granules, the authors proposed that normal melanogenesis may somehow be disrupted by imipramine, leading to the deposition of an abnormal drug metabolite-melanin complex. Sicari et al. and Angel et al. further proposed that because imipramine's chemical structure is so similar to that of chlorpromazine, a drug known to react with UV light to activate tyrosinase and thereby increase melanin production, imipramine may react in a similar manner to induce hyperpigmentation of the skin.

Our patient shares several factors with the previously reported cases of imipramine-induced hyperpigmentation as follows: all patients had been taking imipramine for at least 2 years before onset of hyperpigmentation [7, 8, 9, 10, 11]; hyperpigmentation was both progressive and only seen in sun-exposed areas on the face and bilateral upper extremities; the color of the hyperpigmentation in our patient had a slate-grey appearance similar to that found in all but two cases, which were described as having a prominent brown component of hyperpigmentation [8]; every biopsy obtained stained positive for melanin and negative for iron [7, 8, 9, 10]. Once imipramine was discontinued, normal skin color returned within 1 year in 3 out of 4 reported cases [7, 8, 11] with severe, irreversible hyperpigmentation persisting for over 3 years in one recent report [11]. One case report documents improvement of hyperpigmentation after treatment with Q-switched alexandrite and ruby lasers [16].

Our case along with 10 of the 12 previous cases of hyperpigmentation occurred in a woman [7-15]. The onset of pigmentation occurred at the mean age of 59.7 years in previously reported cases following a mean exposure to imipramine of 10 years. Our patient, a 63 year-old female, noticed her pigmentation after 27 years of imipramine exposure, the longest reported period of imipramine use before onset of hyperpigmentation.


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