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Psychosomatics 2014:55:98–100 & 2014 Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Case Reports
Acute Mania Associated With Levetiracetam Treatment
Eliza M. Park, M.D., Jordan A. Holmes, M.D., Katherine E. Reeder-Hayes, M.D., M.B.A.
evetiracetam is a novel antiepileptic drug used for the hospital, her vital signs were unremarkable with
Received May 10, 2013; revised June 9, 2013; accepted June 10, 2013.From Department of Psychiatry, University of North Carolina, ChapelHill, NC; Department ofMedicine, University of North Carolina, ChapelHill, NC. Send correspondence and reprint requests to Eliza M.Park, M.D., Department of Psychiatry, University of North Carolina,Comprehensive Cancer Support Program, Campus Box 7305, ChapelHill, NC 27599; e-mail: [email protected]
& 2014 Academy of Psychosomatic Medicine. Published byElsevier Inc. All rights reserved.
Lthe treatment of partial and generalized epilepsy.Its mechanism of action is unclear, though it is thoughtto bind to a presynaptic vesicle protein that ultimatelyreduces the synaptic release of glutamate, impedingconduction of epileptic action potentials across thesynapse.1 Levetiracetam is frequently used owing to itsease of oral administration, excellent bioavailability,and low rate of drug interactions as it is not metab-olized by the liver or bound significantly to serumproteins.2,3 Adverse cognitive effects are atypical;however, adverse effects in the central nervous system(CNS) are relatively common, with behavioral symp-toms occurring in up to 16% of patients in randomizedcontrolled trials.4 Frequently reported behavioralsymptoms include depression, hostility, agitation,emotional lability, anger, nervousness, and deperson-alization. Nonbehavioral CNS effects include seda-tion, headache, and asthenia.5 Psychosis is infrequentlyassociated with levetiracetam, occurring in approxi-mately 1% of patients, but well described in multiplecase reports.6,7
Researchers have explored the use of levetirace-tam as a mood stabilizer for treatment of bothdepressive and manic phases of bipolar disorder withmixed results.8–10 Despite the known associationbetween levetiracetam and aggression and irritability,there are no reported cases in the literature oflevetiracetam precipitating manic symptoms. In thefollowing case report, we describe the acute onset ofmania after levetiracetam therapy in a woman with nohistory of mania or hypomania.
Case Report
Ms. B, a 58-year-old woman with stage IV inflamma-tory breast cancer and a remote history of postpartumdepression, was admitted to the cancer hospital forevaluation of brief stuttering spells. On admission to
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the exception of tachycardia (heart rate 120 beats perminute). She did not exhibit any abnormal movementsor tremor and she was no longer experiencing stutter-ing spells. A comprehensive neurologic assessment,including neurology consultation, brain magnetic res-onance imaging (with andwithout contrast), laboratoryworkup, and video electroencephalogram did notreveal any explanatory etiology for her symptoms.Her hospital course was unremarkable and she wasdischarged to homewith a new prescription for levetira-cetam 750 mg twice daily as prophylaxis for possibleseizures. She did not receive any doses of steroids,antihistamines, or antidepressants during her hospitalstay. Two weeks before, she had received oral dexa-methasone as an antiemetic without incident. Shecontinued to take lorazepam1 mgat night as previouslyprescribed. She was originally provided this medication3 months earlier for chemotherapy-associated nausea.
Two weeks later, she presented to the outpatientoncology clinic with symptoms of acute mania. Dur-ing the previous one and a half weeks, she reportedracing thoughts, erratic and impulsive behavior,decreased need for sleep (requiring less than 3 hoursof sleep per night), and emotional lability withirritability. She was paranoid and had called the policeto her home owing to her belief that her son was tryingto harm her and wanted her dead. She was verballyaggressive with strangers and was escorted from localstores by security. She gave away all of her availablespending money to strangers. Upon examination, her
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Park et al.
speech was rapid and hyperverbal. Her affect wasexpansive and she described her mood as “great.” Shewas restless and unable to sit for longer than a fewminutes. Her thought process was tangential withloosened associations. She denied suicidality, homi-cidality, or abnormal perceptions, though she con-tinued to express paranoia toward her son and desireto pursue large purchases, such as a vacation home.She denied any misuse of alcohol or illicit substancesduring this period. Drugs of abuse were not tested asMs. B had no history of substance misuse.
Ms. B and her adult son indicated that she haddiscontinued levetiracetam 3 days before her evalua-tion due to concern that it precipitated her symptoms.Both the patient and her son confirmed that she had nohistory of mania or hypomania before starting levetir-acetam therapy. There was no known family history ofbipolar illness.
Owing to the severity of her symptoms, herlevetiracetam was held and scheduled daytime lora-zepam 1 mg daily and olanzapine 5 mg at night wereadded to her medication regimen. She continued herpreviously prescribed nighttime lorazepam and noadditional medications were used for management ofinsomnia. Within 2 weeks, her behavior had improvedand she resumed her scheduled chemotherapy. Duringthe following month, her olanzapine was discontinuedand lorazepam tapered to her previous dosage withoutincident. She was periodically followed by the psycho-oncology service for 6 subsequent months, and nofurther episodes of mania or hypomania were noted.
Discussion
Levetiracetam is an antiepileptic drug with knownneuropsychiatric adverse effects. To our knowledge,this is the first known report of levetiracetam-inducedmania. Although the mechanism of this adverse effectremains unknown, the temporal relationship betweenemergence and subsequent resolution of symptomswith initiation and cessation of treatment with herantiepileptic medication is compelling. Notably, shewas not treated with concomitant medications, likesteroids, that can precipitate symptoms of mania, andit appears unlikely that her psychiatric symptoms weredue to primary seizure etiology given the negativeneurologic workup.
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In general, psychiatric disorders in patients withepilepsy are common and multifactorial in origin.Patients with a history of psychiatric disorders maydemonstrate an increased susceptibility to the behavioraladverse effects of antiepileptics suggesting an underlyingvulnerability to antiepileptic CNS toxicity.4,11 However,the development of manic symptoms with antiepileptictreatment is unusual. Many, if not most, antiepilepticmedications are also used for their mood-stabilizingproperties. There are several reports that have specifi-cally used levetiracetam for treatment of mania.12,13
Levetiracetam, though, is an antiepileptic drug withuniquemechanismof action andknownassociationwithaggression, hostility, and psychosis. The cause of thesebehavioral effects with levetiracetam remains unknown.
In one prospective study of 553 patients treatedwith levetiracetam, behavioral abnormalities were themost frequently cited reason for prematuremedicationdiscontinuation.14 Known risk factors for the develop-ment of behavioral disturbance with levetiracetaminclude rapid dosage titration, and having a learningdisability, psychiatric history, or symptomatic gener-alized epilepsy.14 Other studies on the relationshipbetween dosage and risk of aggression with levetir-acetam are conflicting.15 In our case, the rapid dosageescalation of levetiracetam as well as her psychiatrichistory may have contributed to her symptomatology.
More research is needed on the mechanisms ofbehavioral disorders with levetiracetam as well asmore specific predictors of which patients are mostsusceptible to these symptoms. Prospective studies oflevetiracetam that use formal psychiatric assessmentsand measurement of irritability and aggression wouldhelp with elucidating this complex relationship. It ispossible that these two symptoms may be reflectiveof an underlying hypomania, mixed mania, or acutemania in patients who develop levetiracetam-associ-ated adverse effects.
Given the increasingly widespread use of thisnewer antiepileptic drug,16,17 clinicians should con-sider close monitoring of patients for treatment-emergent mood and psychotic symptoms, includingthe possibility of mania. In addition, slower titrationrates of levetiracetam, particularly in patients withpsychiatric histories, should be considered.
Disclosure: The authors disclosed no proprietary orcommercial interest in any product mentioned or con-cept discussed in this article.
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Case Reports
References
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