Extended-Release Bupropion–Induced Grand Mal Seizures

CASE REPORT

David J. Rissmiller, DO Thomas Campo, DO

Bupropion hydrochloride is currently available in three for- eration antidepressants. Most seizures occurred within the mulations: immediate-release, sustained-release, and first 6 weeks of treatment.1 Seizures were especially prominent extended-release (ER). Several published reports exist con- when patients took single doses greater than 150 mg or daily cerning bupropion’s history of inducing seizures in both the doses greater than 450 mg. The mean ingested daily dose in immediate- and sustained-release formulations. Although patients who had seizures was 8.3 mg per kilogram of body the potential of the ER formulation for causing seizures is weight.2 In addition, electroencephalographic abnormalities (eg, noted in the drug’s prescribing information, there is no pre- epileptiform discharges) were reported in some patients on viously published report of bupropion ER inducing seizures. bupropion IR therapy.3 In the case reported, a 27-year-old woman who was pre- At dosages of 450 mg/d or less, the incidence rate of scribed bupropion ER as well as clonazepam and lamot- seizures ranged from 0.35% to 0.44%, compared with a first- rigine (anticonvulsants), hydrocodone bitartrate (for irri- seizure incidence of 0.07% to 0.09% in the general popula- table bowel syndrome), and zolipidem tartrate (for tion.4 The estimated seizure incidence was found to increase depression and associated anxiety and insomnia) experi- tenfold at dosages of more than 450 mg/d,5 and the number enced a grand mal seizure 6 months after beginning bupro- of seizure occurrences were twice as high in patients who pion ER therapy. The patient was taken to the emergency took extra doses of bupropion IR on an “as needed” basis.6 In department, where she had a second grand mal seizure 8 fact, a 2002 study7 reported that bupropion-induced seizures hours after the first one. Extended-release bupropion was were the third most common cause of drug-induced seizures discontinued, and the patient had not had additional after cocaine ingestion and benzodiazepine withdrawal. In seizures at 8 months follow-up. addition, about 21% of patients admitted with intentional 8 J Am Osteopath Assoc. 2007;107:441-442 bupropion IR overdose presented with seizures. In 1996, the FDA approved sustained-release bupropion lder tricyclic and monoamine oxidase inhibitor antide- (bupropion SR) as an alternative to bupropion IR. Bupropion Opressants have a dose-dependent potential to decrease SR allowed for more convenient twice daily dosing and seizure threshold. Alternatively, second generation antide- reduced seizure incidence rates to 0.1%.9,10 Published reports, pressants, particularly selective serotonin reuptake inhibitors, however, warn that this long-acting formulation might prolong do not lower seizure threshold and may even have an anti- neurologic toxicity—including seizures in overdose.11 convulsant effect.1 In December 1985, the US Food and Drug Seven years later, in 2003, the FDA approved extended- Administration (FDA) approved bupropion hydrochloride, release bupropion (bupropion ER) as a new, once daily sub- an immediate-release, monocyclic antidepressant structurally stitute for bupropion IR and SR. Bupropion ER was never for- related to amphetamines, as a second generation antidepres- mally evaluated for seizures during premarketing clinical sant. trials,12 and there have been no previously published cases of Soon after the introduction of immediate-release bupro- seizures in patients on the newer ER formulation. The cur- pion (bupropion IR) on the market, patients taking the drug rent case reports an incident of two bupropion ER–induced had higher rates of seizures compared with other second gen- seizures 8 hours apart in the same patient.

Report of Case The patient was diagnosed with chronic irritable bowel syn- From the Department of Psychiatry at the University of Medicine and Den- drome in 1998 and was subsequently prescribed 2 oz of tistry of New Jersey-School of Osteopathic Medicine in Stratford. hydrocodone bitartrate syrup every other day. She continued Address correspondence to David J. Rissmiller, DO, University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine, Department of this treatment for several years. In April 2004, the patient had Psychiatry, 2250 Chapel Ave, Suite 100, Cherry Hill, NJ 08002-2051. her first major depressive episode. Her family physician pre- E-mail: [email protected] scribed the antidepressant mirtazapine, which caused sub- Submitted May 13, 2005; revision received June 13, 2005; accepted June 22, stantial weight gain in the patient and was subsequently dis- 2005. continued. Escitalopram oxalate was then prescribed but later

Rissmiller and Campo • Case Report JAOA • Vol 107 • No 10 • October 2007 • 441 CASE REPORT

discontinued because it caused diarrhea. The physician then 3. Shah GD, Hirsch LJ. Bitemporal epileptiform discharges induced by bupro- prescribed bupropion ER 150 mg/d for 3 weeks, increasing the pion: a case report. Clin Neuropharmacol. 2001;24:304-306. patient’s dosage to 300 mg/d in the fourth week. In addition, 4. Davidson J. Seizures and bupropion: a review. J Clin Psychiatry. 1989;50: the patient’s physician prescribed the anticonvulsants clon- 256-261. azepam (0.5 mg twice daily) and lamotrigine (100 mg/d) as 5. Wellbutrin. In: Physicians’ Desk Reference. 61st ed. Montvale, NJ: Thomson well as zolpidem tartrate (10 mg/d) for depression and asso- Healthcare, Inc; 2007:1603-1607. ciated anxiety and insomnia. 6. Shepherd G. Adverse effects associated with extra doses of bupropion. Phar- Six weeks after beginning this treatment regimen and 2 macotherapy. 2005;25:1378-1382. hours after taking her daily dose of bupropion ER, the patient 7. Pesola GR, Avasarala J. Bupropion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency lost consciousness at work and had a grand mal seizure wit- department. J Emerg Med. 2002;22:235-239. nessed by her coworkers. She was taken to a local emergency 8. Spiller HA, Ramoska EA, Krenzelok EP, Sheen SR, Borys DJ, Villalobos D, et department. al. Bupropion overdose: a 3-year multi-center retrospective analysis [review]. On examination, the patient, a 27-year-old white woman, Am J Emerg Med. 1994;12:43-45. appeared in good health. Physical and neurologic examination 9. Settle EC Jr. Bupropion sustained release: side effect profile [review]. J Clin were unremarkable. Complete blood count, serum analysis, Psychiatry. 1998;59(suppl 4):32-36. and urinalysis laboratory values were normal. She had no 10. Aubin HJ. Tolerability and safety of sustained-release bupropion in the premorbid history of epilepsy or neurologic illness, nor any management of smoking cessation [review]. Drugs. 2002;62(suppl 2):45-52. other known predisposing factors to epilepsy. It was deter- 11. Jepsen F, Matthews J, Andrews FJ. Sustained release bupropion overdose: mined that she should be kept at the hospital for observation. an important cause of prolonged symptoms after an overdose. Emerg Med J. Buproprion was discontinued, but 8 hours after her first 2003;20:560-561. seizure, the patient had a second grand mal seizure, which was 12. Wellbutrin XL. In: Physicians’ Desk Reference. 59th ed. Montvale, NJ: observed by emergency department staff. She was started on Thomson Healthcare, Inc; 2005:1664. intravenous phenytoin sodium and was admitted to the hos- 13. Tutka P, Mróz T, Klucha K, Piekarczyk M, Wielosz M. Bupropion-induced pital for 3 days before being discharged. Results from an elec- convulsions: preclinical evaluation of antiepileptic drugs. Epilepsy Res. troencephalogram were normal. 2005;64:13-22.

Discussion Bupropion, like other antidepressant agents, lowers seizure threshold. This report is the first published case of seizures induced by bupropion ER. Surprisingly, the patient had seizures even though she was taking two anticonvulsants, including clonazepam, which is considered the most efficacious medication in preventing bupropion-induced seizures.13 That her two seizures occurred 8 hours apart may be accounted for by the properties of the ER formulation. Neither zolpidem nor hydrocodone syrup have seizure listed in prescribing information as a possible adverse event. The patient remained on clonazepam, lamotrigine, zolpidem, and hydrocodone, seizure-free, for 8 months after this event. No antidepressant was prescribed in place of bupropion. Although bupropion ER offers the convenience of once- daily dosing, the drug’s prolonged half-life may cause seizures to have a more protracted course, as in the case presented. It is recommended that physicians carefully monitor patients taking any form of bupropion.

References 1. Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in psy- chopharmacological clinical trials: an analysis of Food and Drug Administra- tion (FDA) summary basis of approval reports. Biol Psychiatry. 2007;62:345-354. 2. Heard K, Hurlbut KM. Bupropion. In: Dart RC. The 5-Minute Toxicology Con- sult. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000:278.

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