Depakote

Abstract

Two months after being started on Depakote[R] (divalproex sodium; Abbott Laboratories Inc., Abbott Park, Illinois), a 57-year-old female noticed the development of a transverse yellow band on all 20 proximal nails that eventually led to complete nail plate discoloration. Six to eight weeks after discontinuation of Depakote, normalization of her proximal nail plates was noted.

Other anticonvulsants such as phenytoin and lithium have been documented to lead to nail pigmentation. Although several dermatologic reactions to Depakote have been described, we are not aware of any reported cases of nail discoloration secondary to Depakote.

While our patient did have a history of renal disease with azotemia, we find it highly unlikely to be a contributing factor secondary to the fact that our patient's abnormality did not present similar to the nail abnormalities of renal disease. In conclusion, we found the temporal relationship between Depakote initiation/discontinuation and the nail discoloration to be highly indicative of Depakote as the source.

Other anticonvulsants such as phenytoin and lithium have been documented to lead to nail pigmentation. Although several dermatologic reactions to Depakote have been described, we are not aware of any reported cases of nail discoloration secondary to Depakote.

While our patient did have a history of renal disease with azotemia, we find it highly unlikely to be a contributing factor secondary to the fact that our patient's abnormality did not present similar to the nail abnormalities of renal disease. In conclusion, we found the temporal relationship between Depakote initiation/discontinuation and the nail discoloration to be highly indicative of Depakote as the source.

Case Report

A 57-year-old Latina female presented in October of 2002 with a four month history of yellow nails. Her past medical history was significant for bipolar disorder and progressive renal insufficiency thought secondary to 20 years of lithium toxicity. Earlier that year (April 2002), the patient had been given Depakote[R] (divalproex sodium: Abbott Laboratories Inc., Abbott Park, Illinois) 250 mg PO bid, and two months later noted the development of transverse yellow nail bands involving only the proximal portion of all 20 finger and toenails. The patient reports that the discoloration progressed to involve the entire nail plate of all nails. The remainder of her medication list included Aciphex[R] (rabeprazole sodium), Vioxx[R] (rofecoxib), aspirin, Pravachol[R] (modafinil), and Premarin[R] (conjugated estrogens), all of which the patient had taken for five years or more. There was no family history of discolored nails and the patient neither smoked nor used nail polish. For reasons relating to her primary psychiatric condition, the patient was switched from Depakote to Zyprexa[R] (olanzapine) and six to eight weeks later noted a normalization of color in her proximal nail plates. Her medication regimen had not been otherwise altered.

On physical exam, the patient was found to have a yellow nail-plate discoloration involving 20 nails; her skin exam was otherwise unremarkable. A serum valproate level was not drawn. Notable laboratory values included a serum creatinine level of 1.9, which was unchanged from an assay taken three years prior. A renal scan in March had exhibited decreased bilateral uptake without evidence of obstruction. The patient's liver and lipid profiles were within normal limits, including an albumin level of 3.9. On physical exam, she was found to have a distal yellow discoloration of all twenty nails with normal nail plates observed proximally (Figure 1). Several months later, while off Depakote therapy, her nails resumed their normal appearance (Figure 2).

[FIGURE 1 OMMITTED]

[FIGURE 2 OMMITTED]

Discussion

Depakote is an anti-convulsant commonly used for the treatment of absence and complex partial seizure disorders. More recently, this agent has been used successfully in the treatment of mania associated with bipolar disorder (1). Depakote's mechanism of action is not fully understood; however, the drug is thought to increase central nervous system (CNS) levels of gamma-aminobutyric acid (GABA) by inhibiting catabolic enzymes in the synaptic cleft (2).

Treatment with Depakote is generally well-tolerated by patients. Patients are typically started on 250 to 500 mg twice daily. Common dose-related side effects include tremors, sedation, fatigue, and ataxia (3). Depakote has also been associated with pancreatitis, thrombocytopenia, and transaminitis, usually within the first 6 months of therapy. Dermatologic reactions to Depakote are unusual; however, there have been reports of Stevens-Johnson syndrome (4), a pellagra-like syndrome secondary to an induced nicotinic acid deficiency (5), and alopecia and hair texture changes. These side effects are rarely severe enough to necessitate the drug's discontinuance.

There are other anticonvulsant agents that have been associated with abnormal nail pigmentation. Phenytoin has been reported to turn the nail plate brown, while lithium has reportedly turned one patient's nails from golden-yellow to normal. To our knowledge, this is the first reported case of nail discoloration due to Depakote therapy. There is a single report of Depakote causing onycholysis, which was not observed in our patients.

Renal disease with resultant azotemia, as seen in our patient, may also result in abnormal nail pigment. These so-called 'half-and-half nails' are characterized by a normal nail proximally, a sharp line of demarcation, and a red-brown distal haW. Half-and-half nails, however, are not yellow, nor do they spontaneously remit during sustained azotemia. The temporal relationship between the patient's initiation of Depakote therapy and the return of her normal nail color following its withdrawal suggest a causative relationship.

References

(1.) Ford MD. Clinical Toxicology, 2001, Philadelphia, Saunders.

(2.) Holland KD. Efficacy, pharmacology, and adverse effects of antiepileptic drugs. Neurol Clin 2001; 19:313-45.

(3.) Goldberg JF. New drugs in psychiatry. Emerg Med Clin North Am 2000; 18:211-31.

(4.) Drielus FE. Valproic acid toxicity. In Levy RH, Mattson RH, Meldrum BS. Antiepileptic Drugs. 1995, Raven Press, New York.

(5.) Gillman MA, Sandyk R. Nicotinic acid deficiency induced by sodium valproate. S Afr Med J 1984; 65:986.

(6.) Jeavons PM. Clark JE, Harding GF. Valproate and curly hair. Lancet 1977; 1:359.

(7.) Litt JZ. Drug Eruption Reference Manual, 2000, CRC Press-Parthenon Publishers, New York.

(8.) Grech V, Vella C. Generalized onycholysis associated with sodium valproate therapy. Eur Neurol 1999; 42:64-5.

(9.) Lindsay PG. The half-and-half nail. Arch Intern Med 1967; 119:583-7

ROBERT BUKA MD, RACHEL HILLE MD, PATRICIA MCCORMACK MD

DEPARTMENT OF DERMATOLOGY, NEW YORK MEDICAL COLLEGE

VALHALLA, NEW YORK

DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY OF NORTH DAKOTA SCHOOL OF

MEDICINE

FARGO, NORTH DAKOTA

ADDRESS FOR CORRESPONDENCE:

Rachel Hille MD

Department of Medicine

University of North Dakota School of Medicine

1034 44th St. SW #302

Fargo. ND 58103

T: (701) 306-6757

F: (701) 293-4145

E: rhille@medicine.nodak.edu

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