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Zonisamide (brand name Zonegran®) is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures. It was discovered by researchers at Dainippon Sumitomo Pharma (大日本住友製薬: Dainippon Sumitomo Seiyaku (formerly Dainippon Pharmaceutical (大日本製薬: Dainippon Seiyaku)), who launched it in 1989 as Excegran® in Japan. It was marketed by Élan in the United States starting in 2000 as Zonegran®, before Élan transferred their interests in zonisamide to Eisai (エーザイ) in 2004. more...

Zoledronic acid

Eisai also markets Zonegran® in Asia (China, Taiwan, and fourteen others) and Europe (starting in Germany and the United Kingdom).



Zonisamide is approved in the United States, United Kingdom, and Japan for adjunctive treatment of partial seizures in adults.


An open trial on zonisamide in seven Parkinson's disease patients had positive results, according to this 2001 report. Since then, it has been reported to treat the resting tremor that other therapies may leave behind. By early November of 2005, Dainippon Sumitomo had filed a NDA for the use of zonisamide in Parkinson's disease; it is to be marketed as Tremode®.


Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5, to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.

Mechanism of Action

The exact mechanism of action is not known for zonisamide. According to Leppik, while zonisamide may be a carbonic anhydrase inhibitor like acetazolamide, this is not one of the primary mechanisms of action, which might be blocking repetitive firing of voltage-gated sodium channels and reduction of T-type calcium channel currents, or by binding allosterically to GABA receptor like the benzodiazepines and muscimol, or increasing the levels of the glutamate transport protein in the brain while decreasing the amount of GABA transport protein, in other words, inhibiting the uptake of the inhibitory neurotransmitter GABA while enhancing the uptake of the excitatory neurotransmitter glutamate.


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Mitigating Cognitive Side Effects Associated with Topiramate
From Perspectives in Psychiatric Care, 4/1/05 by Antai-Otong, Deborah

This column offers a question-and-answer forum to help nurses maintain their knowledge of advances in prescribing and psychopharmacology, and implications for safe psychiatric care. Send your questions related to prescribing psychotropic medications to the Editor, Mary Paquette, at

Questions: Ms. Antai-Otong, when using topiramate as a mood stabilizer, I have experienced general complaints of cognitive slowing, memory problems, etc. Please explain the neurobiology of this and give some suggestions for dosing versus discontinuation.

Deborah Antai-Otong responds: Topiramate is a newer anticonvulsant that shares similar pharmacotherapeutic effects with other mood stabilizers such as valproate, lamotrigine, and carbamazepine (Maidment, 2002). It enhances gamma aminobutyric acid (GABA) activity, modulates calcium channels, and antagonizes glutamatergic transmission (Chengappa, Gershon, & Levine, 2001). Early evidence indicates that it is useful as monotherapy and adjunctive therapy with other mood stabilizers in the treatment of bipolar I and II (Chengappa et al., 2001; Gupta, Masand, Frank, Lockwood, & Keller, 2000; Mclntyre, Mancini, McCann, Srinivasan, Sagman, & Kennedy, 2002). Topiramate has a favorable side effect profile and is generally well tolerated due to minimal protein binding, low hepatic metabolism and primarily unaltered renal excretion, a 24-hour half-life, and negligible drug interactions. While some clients with bipolar disorder exhibit minimal adverse effects, some experience distressful cognitive side effects, particularly language disturbances. Most data indicate specific language impairment as verbal fluency and word finding difficulties. Language impairments have been largely associated with high dosage and rapid titration schedules (Lee, Sziklas, Andermann, et al., 2003; Ojemann, Ojemann, Dodrill, Crawford, Holmes, & Dudley, 2001).

The precise mechanism of cognitive impairment is not yet fully understood; however, preclinical evidence links them to their action on GABA potentiation and glutamate receptor antagonism at the N-methyl-Daspartate (NMDA) receptors the potentiating action of this medication at the level of the neurotransmission system of GABA, a substance that produces inhibitory actions in the frontal lobe (Petty, 1995; LaRoche & Helmers, 2004).

Although the majority of clients exposed to topiramate are adults with partial-seizure disorders, growing data indicate its efficacy in treating bipolar disorders. A major problem with these data was the rapid titration of toparimate, with an initiation dose of 100 mg/ day with weekly increments of 100 to 200 mg/day to dosages as high as 1000 mg/day.

Other researchers support findings that link high doses and rapid titration with cognitive impairment and indicate that prescribing 400 to 600 mg/day or relatively rapid titration to maintenance dose in 3 to 4 weeks increases the risk of these adverse effects (Baeta, Santana, Castro, et al., 2002; Shorvon, 1996). In a multicenter, double-blind trial of 188 clients randomized to either a low dose and slow titration schedule and a high dose and rapid titration, Biton, Edwards, Montouris, et al. (2001) found that adults with partial-onset seizures in the former group experienced significantly less cumulative cognitive impairment than those in the latter group. They also surmised that slower titration with an initial dose of 50 mg and 50 mg weekly increments resulted in fewer adverse effects than an initial dose of 100 mg and weekly increments of 100-200 mg of topiramate. Although there is growing evidence that links cognitive impairment with high dosages and rapid titration, some clients may idiosyncratically develop adverse side effects at very low doses (Andrade, 2001).

In general, the suggested target dose in epilepsy is 400 mg/day in b.i.d. divided doses; the precise dose for persons with bipolar disorder has not been established. However, studies show drug efficacy with a range of 100 to 400 mg/day in b.i.d. doses in the treatment of bipolar disorders (Spina & Perugi, 2004; Yatham, 2004).

Suggested Dose and Titration Schedule

The following recommendations may minimize the cognitive side effects associated with topiramate:

* Make an accurate diagnosis and monitor mood symptoms using the Young Mania Rating Scale (YMRS) and depression scale [response defined as >50% reduction of symptoms], such as the 17-item Hamilton Depression Rating Scale (HDRS).

* Begin with an initial dose of 25 mg/day χ week (Evins, 2003; Lykouras & Hatzimanolis, 2004; McIntyre, et al, 2002).

* Slowly titrate or increase dose by 25 to 50 mg (divided dose-bid) every 3-7 days, as clinically indicated and tolerated (adverse effects), not to exceed 400 mg/day b.i.d. [target dose 200-400 mg/day (divided bid dosing)] Grunze Normann, Langosch, et al., (2001).

* Monitor weekly for one month, biweekly in the second month and thereafter to assess clinical response and adverse effects.


Albeit there is no consensus about dosing and titration, this article offers salient points to mitigate topiramateinduced cognitive side effects. However, the decision to discontinue or reduce the dose of topiramate to mitigate cognitive side effects must be individualized and based on client preferences, medication efficacy, and side effects. Psychiatric nurses must initiate treatment interventions, such as a minimum starting dose, b.i.d. dosing, slow titration, and close monitoring.


Andrade, C. (2001). Confusion and dysphoria with low-dose topiramate in a patient with bipolar disorder. Bipolar Disorder, 3, 211-212.

Baeta, E., Santana, I., Castro, G., Goncalves, S., Goncalves, T., Carmo, L, & Carito, A.I. (2002). Cognitive effects of therapy with topiramate in patients with refractory partial seizures. Revieio of Neurology, 34, 737-741.

Biton, V., Edwards, K.R., Montouris, G.D., Sackellares, J.C., Harden, C.L., Kamin, M., Topiramate, & TPS-TR Study Group (2001). Topiramate titration and tolerability. The Annals of Plmrmacotherapy, 35, 173-179.

Chengappa, K.N.R., Gershon, S., & Levine, J. (2001). The evolving role of topiramate among mood disorders in the management of bipolar disorder. Bipolar Disorder, 3, 215-232.

Evins, A.E. (2003). Efficacy of newer anticonvulsant medications in bipolar spectrum mood disorders. Journal of Clinical Psychiatry, 64 (suppl. 8), 9-14.

Grunze, H.C., Normann, C., Langosch, }., Schaefer, M., Amann, B., Sterr, A., Schloesser, S., Kleindienst, N., & Walden, J. (2001). Journal of Clinical Psychiatry, 62, 464^68.

Gupta, S., Masand, P.S., Frank, G.L., Lockwood, K.L., & Keller, P.L. (2000). Topiramate in bipolar and schizoaffective disorders: Weight loss and efficacy. Primary Care Companion. Journal of Clinical Psychiatry, 2, 96-100.

LaRoche, SM. & Helmers, S.L. (2004). The new antiepileptic drugs: Scientific review. Journal of the American Medical Association, 297, 605-614.

Lee, S., Sziklas, V., Andermann, F., Farnham, S., Risse, G., Gustafson, M., Gates, J., Penovich, P., Al-Asmi, A., Dubeau, F., & Jones-Gotman, M. (2003). The effects of adjunctive topiramate on cognitive function in patients with epilepsy. Epilcpsia, 44, 339-347.

Lykouras, L. & Hatzimanolis, J. (2004). Adjunctive topiramate in the maintenance treatment of bipolar disorders: An open-label study. Current Medical Research and Opinion, 20, 843847.

Maidment, LD. (2002). The use of topiramate in mood stabilization. Annals of Pharmacotherapy, 36, 1277-1281.

McIntyre, R.S., Mancini, D.A., McCann, S., Srinivasan, J., Sagman, D., & Kennedy, S.H. (2002). Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: A preliminary single-blind study. Bipolar Disorder, 4, 207-213.

Ojemann, L.M., Ojemann, G.A., Dodrill, C.B., Crawford, C.A., Holmes, M.D., & Dudley, D.L. (2001). Language disturbances as side effects of topiramate and zonisamide therapy. Epilepsy Behavior, 2, 579-584.

Petty, F. (1995). GABA and mood disorders: A brief review and hypothesis. Journal of Affective Disorders, 34, 275-281.

Shorvon, S. (1996). Safety of topiramate: Adverse events and relationships to dosing. Epilepsia, 37 (suppl. 2), S18-S22.

Spina, E. & Perugi, G. (2004). Antiepileptic drugs: Indications other than epilepsy. Epileptic Disorders, 6, 57-75.

Yatham, L.N. (2004). Newer anticonvulsants in the treatment of bipolar disorder. Journal of Clinical Psychiatry, 65 (suppl. 10), 2835.

Deborah Antai-Otong, MS, APRN, BC, FAAN

Author contact:, with a copy to the Editor:

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