Eruptive Xanthomas Associated with Olanzapine Use

OBSERVATION Eruptive Xanthomas Associated With Olanzapine Use

Howard Y. Chang, MD, PhD; Todd W. Ridky, MD, PhD; Alexandra B. Kimball, MD, MPH; Elizabeth Hughes, MD; Anthony E. Oro, MD, PhD

Background: Since their introduction to the US market, sufficiency, after starting olanzapine therapy. These cases atypical antipsychotic drugs, such as olanzapine, have been further support the association of severe dyslipidemia with widely prescribed for the management of psychosis and have olanzapine use in selected patients. increasingly been used in dermatologic settings for the treatment of psychogenic dermatoses. Mild hyperglycemia and Conclusion: With the increasing use of atypical anti- hypertriglyceridemia have been documented from the use psychotic agents in the dermatologic setting, the dyslip- of these medications, but the range of effects on metabo- idemia that develops in association with olanzapine use lism and the effects on skin are poorly characterized. emphasizes the need for periodic metabolic studies in high-risk patients. Observation: We describe 3 patients who developed eruptive xanthomas, 1 of whom had relative insulin in- Arch Dermatol. 2003;139:1045-1048

INCE THEIR introduction to the thisia, as well as cardiotoxic effects at high US market, atypical neurolep- dosages.20-22 These adverse effects are not tic agents, such as olanza- associated with the use of atypical anti- pine, have been widely pre- psychotic drugs, making them an attrac- scribed for the management of tive treatment alternative. However, the use psychosis.S They are considered atypical be- of atypical antipsychotic agents is rela- cause of their altered affinities for seroto- tively recent, and their dermatologic ef- nin and dopamine receptors, and they have fects are not well established. Herein, we an improved adverse effect profile com- describe 3 unrelated patients who devel- pared with older agents.1-4 While effec- oped eruptive xanthomas after starting tive, the agents have repeatedly been shown olanzapine therapy, illustrating the po- to cause mild hyperglycemia and hypertri- tential for severe dyslipidemia to develop glyceridemia.5-11 Although the effects on in association with drug use. glucose and lipid metabolism are well documented, the range of glucose and lipid ab- REPORT OF CASES normalities is less well characterized. In some individuals, initiation of treatment has CASE 1 been shown to induce latent diabetes, ketoacidosis, and hyperosmolar coma.9,12-16 A 31-year-old white man with schizophre- Atypical antipsychotic agents are in- nia presented with a 5-week eruption of creasingly being used in the primary care hundreds of yellowish umbilicated pap- setting. In a study from the United King- ules on his arms, legs, and trunk. He was dom, they make up 1% of all primary care also taking several long-term psychiatric drug expenditures, and the number of pre- medications, including clomipramine, ci- scriptions has increased 6-fold over a talopram, trihexyphenidyl, methylpheni- 5-year period.17 In dermatology, these date, and buspirone and had begun taking drugs have shown efficacy in the treat- olanzapine 8 weeks earlier. He had a fam- ment of psychogenic dermatoses such as ily history of diabetes mellitus but no per- From the Department of delusions of parasitosis and chronic pru- sonal history of diabetes or glucose intol- Dermatology, Program in 18-20 Epithelial Biology, Stanford rigo nodularis. The current treatment erance. Multiple 2- to 6-mm, yellowish, University School of Medicine, of choice is the antipsychotic medication erythematous, firm, nontender papules Stanford, Calif. The authors pimozide. However, pimozide’s effective- were noted on his trunk and extremities but have no relevant financial ness is limited by extrapyramidal symp- spared his palms and soles (Figure 1A, C, interest in this article. toms such as tardive dyskinesia and aka- and F). Acanthosis nigricans was noted on

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C D

E F

G H

Figure 1. Eruptive xanthomas after the initiation of olanzapine therapy. The lesions appear diffusely on the trunk (patient 1, A; patient 3, B), extremities, including the elbows, and ears (patient 1, C; patient 3, D and E). The lesions show koebnerization at the site of injury, eg, a cat scratch on the wrist (F). Acanthosis nigricans was seen in the flexural regions of the arms, legs, and feet (patient 1, G and H [arrows]).

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Figure 2. Histologic features of eruptive xanthomas in patients taking olanzapine. A, Low-power field showing dermal cell proliferation of lipid-filled cells. B, Higher-power view revealing the benign-appearing cellular proliferation of lipid-filled macrophages seen in xanthomas (arrow).

Patient Characteristics

Patient No./ Family History Dosage of Time at Triglycerides, Cholesterol, Serum Acanthosis Age, y/Sex Diagnosis of Diabetes Olanzapine, mg Onset, mo mg/dL mg/dL Glucose, mg/dL Xanthomas Nigricans 1/30/M Schizophrenia Yes 10 6 3220 607 370 Yes Yes 2/21/M Schizophrenia No Unknown 2 5907 544 358 Yes No 3/52/F Schizophrenia No 10 3 7210 1090 Not determined Yes No and anxiety

SI conversion factors: To convert triglycerides, cholesterol, and glucose to millimoles per liter, multiply by 0.0113, 0.0259, and 0.0555, respectively.

the inner aspect of his arms and the dorsal aspect of both of gemfibrozil and fenofibrate to control his hyperlipid- feet (Figure 1G and H). emia. He was subsequently confirmed to have type II dia- A punch biopsy specimen confirmed the diagnosis of betes by serial abnormal glucose tolerance test results and eruptive xanthomas (Figure 2). Laboratory studies re- a hemoglobin A1c level of 16.4.%. Metformin therapy was vealed severe hyperglycemia and hypertriglyceridemia subsequently initiated. However, the patient was poorly (Table), and the patient was sent to the emergency de- compliant with both therapies, and to date he still has partment for evaluation and treatment of new-onset dia- hyperlipidemia and persistent eruptive xanthomas. betes mellitus. He had no detectable antibodies to pancreatic islet cells or insulin, but the insulin C peptide level was CASE 3 elevated at 3.6 ng/mL (1.2 nmol/L) (reference range, 0.6- 2.7 ng/mL [0.2-0.9 nmol/L]). His hyperglycemia was rap- A 50-year-old Filipino woman with schizophrenia pre- idly reversed with intravenous insulin, and glyburide therapy sented with a 3-month history of an eruption of mul- was initiated. His hyperglycemia and hypertriglyceride- tiple painless papules on her arms, shins, and abdomen. mia were normalized, and the xanthomas resolved after 1 Her antipsychotic therapy had been changed from ris- month despite the continuation of olanzapine therapy. peridone to olanzapine some months before the visit, and she was also taking trihexyphenidyl and diphenhy- CASE 2 dramine. She had no family or personal history of diabetes mellitus. Her skin contained many 2- to 4-mm, or- A 21-year-old man with schizophrenia presented with a ange-yellow, firm papules on her abdomen and the 2-month history of a progressive eruption of firm, yellow- extensor surface of both arms and shins. white papules on his arms, trunk, and face (Figure 1B, A punch biopsy specimen obtained from an abdomi- C, and E). Olanzapine therapy had been initiated sev- nal lesion showed a dermal infiltrate of foamy cells and eral weeks earlier. He was also being treated with fluox- confirmed the diagnosis of eruptive xanthoma. The meta- etine, bupropion, buspirone, and gabapentin. He had no bolic workup revealed severe hyperglycemia and hyper- family history of diabetes mellitus. His skin contained hun- triglyceridemia (Table). Simvastatin therapy was initi- dreds of 2- to 3-mm, white-yellowish, firm papules on ated, but the patient was subsequently unavailable for the helix of his ears, back, arms, and legs. follow-up. A punch biopsy specimen from a right shoulder lesion demonstrated lipid-laden macrophages that were di- COMMENT agnostic for eruptive xanthomas. Metabolic workup revealed markedly elevated serum glucose and triglyceride The skin has long been known to reflect the metabolic levels (Table), and the patient was started on a regimen state of the body, with derangements giving rise to a

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 variety of dermatoses. Atypical antipsychotic agents Accepted for publication December 16, 2002. such as olanzapine are known to cause mild hypergly- Corresponding author: Anthony E. Oro, MD, PhD, Cen- cemia and hypertriglyceridemia. This case series shows ter for Clinical Sciences Research, Stanford University, 269 that, in select individuals, olanzapine therapy can cause Campus Dr, Room 2145, Stanford, CA 94305 (e-mail: insulin insufficiency, hyperglycemia, and dyslipidemia, [email protected]). leading to eruptive xanthomas. These adverse effects can be most easily explained by olanzapine’s effects on REFERENCES insulin action, which is known to regulate glucose and lipid metabolism.23 1. Goodnick PJ, Kato MM. Antipsychotic medication: effects on regulation of glucose and lipids. Expert Opin Pharmacother. 2001;2:1571-1582. 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