Letters to the Editor
Zonisamide Treatment of Bipolar Disorder: A Case Report
As far back as 1971, carbamezapine was used to treat acute mania (1). In 1995, the FDA approved divalproex sodium for the treatment of patients presenting with acute mania. Over the last few years, newer anticonvulsants have been used to treat bipolar disorder (BD); these include gabapentin, lamotrigine, oxcarbazepine, and topiramate (2). In March 2000, the FDA approved zonisamide—a drug chemically unrelated to other anticonvulsants (3)—for the treatment of partial seizures in adults. I present a case in which a patient with BD was tried on numerous conventional mood-stabilizing agents and stabilized on zonisamide. I believe this to be the first reported case since zonisamide’s release in the US.
Mr A, aged 51 years, has a 27-year history of BD type I. His most recent episode was hypomanic. His illness significantly impaired him over the years, and he had multiple hospitalizations. Over the years, he took various medications, including lithium, carbamezapine, gabapentin, valproic acid, haloperidol, thioridazine, bupropion, fluoxetine, and nortriptyline. On initial presentation, Mr A was taking a combination of venlafaxine extended release (XR) 300 mg daily, mirtazapine 60 mg daily, quetiapine 200 mg daily, and topiramate 100 mg twice daily. His depressive symptoms with concomitant anxiety had stabilized over a 5-month period. He began to experience hypomanic symptoms, scoring 17 on the Young Mania Rating Scale (YMRS) (4), despite increasing his topiramate to 200 mg twice daily. An adjunct mood stabilizer, zonisamide was added at a dosage of 100 mg daily, with the patient giving informed consent for this off-label use. Zonisamide was increased by 100 mg after 2 weeks. At the end of 1 month, the patient was taking 300 mg daily, and his YMRS score was 3. Initially, he experienced sedation but otherwise tolerated the addition of zonisamide without problems. After stabilization, his zonisamide plasma level was 13.8 ug/ml. The topiramate was tapered off over 1 month, with no adverse effects. At 4 months, Mr A remains stable.
Zonisamide has been commercially available in Japan since 1989. It has been studied in an open-label, add-on fashion in the treatment of patients with acute mania. In this group, 33% of patients with bipolar mania showed remarkable improvement, while 80% of patients with BD had more-than-moderate global improvement (5). Zonisamide is a 1,2-benisoxazole-3-methanesulfonamide chemically distinct from other antiepileptic agents (6). It has several mechanisms of action: it blocks sensitive sodium channels and T-type calcium channels, it scavenges hydroxyl and nitric oxide radicals, and it enhances dopamine function (7). It also has GABAergic properties (2) and is reported to be structurally similar to serotonin (5). The prescribing information does not give recommendations for monitoring zonisamide, nor does it give a therapeutic range (3). Lepke and others determined that patients taking between 100 and 400 mg daily had plasma levels ranging from 7 to 40 ug/ml, with the mean ranging from 13 to 20 ug/ml (8). Zonisamide may prove to be a valuable addition to the ever-growing number of mood stabilizing agents used to treat BD, but it needs more controlled study. A case report exists of zonisamide-induced mania in a patient with an underlying seizure disorder and a history of an open head injury (9). Zonisamide should not be used in patients with a sulfonamide sensitivity, and patients should give informed consent for off-label uses of medications.
1. Takezaki H, Hanaoka M. The use of carbamezapine (Tegretol) in the control of manic- depressive psychosis and other manic-depressive states. Seishin Igaku 1971;13:173–83.
2. McElroy SL, Keck PE Jr. Pharmacologic agents for the treatment of acute bipolar mania. Biol Psychiatry 2000;48:539–57.
3. Élan Pharmaceuticals. South San Francisco, (CA): Élan Pharmaceuticals; 2001. Data on File.
4. Young RC, Biggs JT, Ziegler VE, Meyers DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978:133:429–35.
5. Kanba S, Yagi G, Kamijima K, Suzuki T, Tajima O, Osaki J. The first open study of zonisamide, a novel anticonvulsant shows efficacy in mania. Prog Neuropsychopharmacol Biol Psychiatry 1994;18:707–15.
6. Schmidt D, Jacob R, Loiseau P, Deisenhammer E, Klinger D, Despland A. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res 1993;15:67–73.
7. McAuley JW, Biederman TS, Smith JC, Moore JL. Newer therapies in the drug treatment of epilepsy. The Ann Pharmacother 2002;36:119–29.
8. Lepke I, Shah J, Shellenberger K. Zonisamide pharmacokinetics: direct relationship between oral dose and blood levels. Epilepsia 1999;40 (Suppl 2): 286.
9. Charles CL, Stoesz L, Tollefson G. Zonesamide-induced mania. Psychosomatics 1990;31:214–7.
Timothy R Berigan, DDS, MD