Obsessive-Compulsive Behavior Induced by Levetiracetam

Journal http://jcn.sagepub.com/ of Child Neurology Obsessive-Compulsive Behavior Induced by Levetiracetam Mayu Fujikawa, Yuri Kishimoto, Yosuke Kakisaka, Kazutaka Jin, Kazuhiro Kato, Masaki Iwasaki and Nobukazu Nakasato J Child Neurol published online 9 July 2014 DOI: 10.1177/0883073814541471 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/07/08/0883073814541471 Published by: http://www.sagepublications.com Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav >> OnlineFirst Version of Record - Jul 9, 2014 What is This? Downloaded from jcn.sagepub.com at TOHOKU UNIVERSITY MEDICAL LIB on July 14, 2014 Brief Communication Obsessive-Compulsive Behavior Induced by Levetiracetam Journal of Child Neurology 1-3 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814541471 jcn.sagepub.com Mayu Fujikawa, PhD1, Yuri Kishimoto, BA1, Yosuke Kakisaka, MD1, Kazutaka Jin, MD1, Kazuhiro Kato, MD2, Masaki Iwasaki, MD3, and Nobukazu Nakasato, MD1 Abstract A novel antiepileptic drug, levetiracetam, has been reported to cause several psychiatric adverse effects in spite of its effectiveness on epilepsy. However, a possible relationship between levetiracetam and obsessive-compulsive behavior has only been reported in a few studies with adult epilepsy patients. We treated a pediatric patient with epilepsy without past or family history of psychiatric disorder. Levetiracetam was started to control generalized tonic-clonic seizure. Two months after initiation of levetiracetam with favorable seizure control, she started to show an obsessive-compulsive behavior such as repetitive checking of her back, pants, and chair. Based on the course of its appearance, levetiracetam administration was identified as a possible cause. After termination of levetiracetam, her obsessive-compulsive behavior completely disappeared with reappearance of seizures. This case provides clear evidence that levetiracetam may cause obsessive-compulsive behavior even in a pediatric epilepsy patient without psychiatric background, possibly mediated by modulation of the glutamate system by levetiracetam. Keywords obsessive-compulsive behavior, levetiracetam, glutamate Received April 01, 2014. Received revised May 10, 2014. Accepted for publication June 01, 2014. Levetiracetam is a novel antiepileptic drug effective against both symptomatic and idiopathic epilepsy. Several psychiatric adverse effects have also been reported including agitation and hostility.1 However, the possible relationship between levetiracetam administration and obsessive-compulsive behavior has only been reported in a limited number of articles.2,3 Obsessive-compulsive disorder is characterized by intrusive thoughts that cause uneasiness, apprehension, fear, or worry (obsession) and/or repetitive behaviors aimed at reducing the associated anxiety (compulsion).4 These behaviors sometimes emerge as a result of direct physiological effect of a substance. Here, we present a pediatric patient with epilepsy who exhibited obsessive-compulsive behaviors exclusively during levetiracetam administration. 1000 mg was added from the age of 12 years 10 months (Figure 1). However, this dosage failed to control her seizures, so the dose was increased to 1500 mg at the age of 13, and her seizures disappeared. Two months later, she started to exhibit a compulsive behavior such as repetitive checking of her back, pants, and chair. She was aware that these repetitive actions were meaningless, yet she could not stop. Neurologic examination was unremarkable. Magnetic resonance imaging found no abnormalities. Her intelligence quotient evaluated with the Wechsler Intelligence Scale for Children, 3rd edition, was 106 for verbal intelligence quotient, 122 for performance intelligence quotient, and 115 for full intelligence quotient. The Children’s Yale-Brown Obsessive Compulsive Scale administered scored Case Presentation 1 A 14-year-old right-handed female with normal intellectual development started to have epileptic seizures, manifesting as conscious impairment and occasionally leading to generalized tonic-clonic seizures, from the age of 4. She had no family history of psychiatric disorder or epilepsy, or past history of psychiatric disorder. Carbamazepine administration had controlled her seizures for 5 years. She suffered generalized tonic-clonic seizures again at the age of 10. Levetiracetam administration Department of Epileptology, Tohoku University School of Medicine, Sendai, Miyagi, Japan 2 Department of Neurology, Tohoku University School of Medicine, Sendai, Japan 3 Department of Neurosurgery, Tohoku University School of Medicine, Sendai, Japan Corresponding Author: Yosuke Kakisaka, MD, Department of Epileptology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. Email: [email protected] Downloaded from jcn.sagepub.com at TOHOKU UNIVERSITY MEDICAL LIB on July 14, 2014 2 Journal of Child Neurology Figure 1. Clinical course during the levetiracetam therapy. Two months after increasing the dose of levetiracetam to 1500 mg, the patient started to show obsessive-compulsive behavior, which disappeared after levetiracetam termination. Seizures were well controlled only during administration of levetiracetam 1500 mg. her as 13 (mild symptom).5 Based on comprehensive understanding of the patient’s psychiatric condition, levetiracetam administration was identified as a possible cause. When levetiracetam administration was terminated, her obsessive-compulsive behavior completely disappeared. The score of the Children’s Yale-Brown Obsessive Compulsive Scale has also been reduced to zero. However, complete freedom from seizures has not been achieved so far with other antiepileptic drugs. Discussion The present report is the first pediatric case of obsessivecompulsive behavior due to administration of levetiracetam, clearly presenting the causal relationship in terms of presence of comorbidities. In one adult case, a 21-year-old male, with mild intellectual disability, pervasive developmental disorder, and epilepsy, had developed obsessive-compulsive behavior caused by levetiracetam.2 Topiramate administration had initially failed to control his seizures, so levetiracetam administration was begun. He had developed a new interest in making index cards after the dose of levetiracetam was increased up to 1500 mg, although the exact temporal relationship between levetiracetam dose increase and the start of the obsessivecompulsive behavior was not established. This case identified levetiracetam as a possible cause, as tapering of levetiracetam resulted in disappearance of his obsession. Another report also describes the obsessive-compulsive phenomenon during levetiracetam administration in a sample of 35 adult epilepsy patients with cognitive impairment.3 The frequency and severity of ritualistic behaviors were reported significantly higher during the period with the medication. However, these reports failed to recognize the possible involvement of comorbid intellectual and other developmental conditions in relation to obsessive-compulsive behaviors. The medication effect on psychiatric symptoms is generally complex when a patient has underlying comorbid conditions. In contrast, our case clearly demonstrated a relationship between the medication and the obsessive-compulsive behavior in 2 aspects: (1) the beginning and termination of levetiracetam administration were correlated with the appearance and disappearance of the behavior, and (2) our patient was intellectually intact without underlying psychiatric condition. Therefore, this case provides possible implication for physicians to consider obsessive-compulsive behavior as one of rare side effects of levetiracetam. We speculate that the obsessive-compulsive behavior in our case was caused by the pharmacologic action of levetiracetam. Levetiracetam is reported to bind to a synaptic vesicle protein, SV2A, which is understood to be the main mechanism for the antiepileptic action through a modulative effect on the glutamate system by controlling the release of glutamate from presynaptic neurons.6 Recent studies have shown that obsessive-compulsive disorder may be associated with altered glutamate neurotransmission.7,8 A lower concentration of glutamate has been noted in the anterior cingulate region of patients with obsessive-compulsive disorder,9 as well as possible glutamate system dysregulation in the orbitofrontal region.10 Therefore, glutamate neurotransmission-modulating agents may cause obsessive-compulsive disorder.8 Contrarily, some investigators suggested the opposite effect of levetiracetam, potentially efficacious for obsessive-compulsive disorders in a subset of patients, especially with body dysmorphic disorder.11,12 Yet, lack of research fails to establish efficient hypothesis for these opposite psychiatric effects of levetiracetam. We speculate that modulational, neither agonistic nor antagonistic, role of the agent for glutamate system has the potential to cause diverse sequence of levetiracetam-associated behavior change. The reasons for the appearance of obsessive-compulsive behavior 2 months after initiation of levetiracetam 1500 mg remain unknown in our case. Although common psychotropic side effects of levetiracetam may appear soon after beginning the administration,13 this obsessive-compulsive behavior may have a different course of appearance. Levetiracetam may have various, both positive and negative, psychotropic effects on patients. A study of 288 epilepsy patients treated with levetiracetam found positive or negative effects in 22% and 37% of the patients, respectively.1 The Downloaded from jcn.sagepub.com at TOHOKU UNIVERSITY MEDICAL LIB on July 14, 2014 3 Fujikawa et al positive effects on behavioral changes are not related to type of epilepsy, cotherapy, levetiracetam dose, drug load, or psychiatric history. In contrast, the negative effects are associated with poorer seizure control, mental retardation, indicators of organic psychosyndrome, and nonplanning impulsiveness.1 The aggressiveness of levetiracetam might be partially explained by induced changes in sleep characteristics,13 although the precise mechanism has been unknown. The psychotropic effects of levetiracetam may have multiple mechanisms and may be affected by underlying conditions. Nevertheless, physicians should be aware of possible presence of the peculiar condition due to levetiracetam even when a patient has no psychiatric background. Further experience with similar cases may help to elucidate the mechanism of this rare side effect. Acknowledgment We thank Drs. W.K. Goodman, S.A. Rasmussen, and L.H. Price for their permission to use the Children’s Yale-Brown Obsessive Compulsive Scale. Author Contributions MF, YuK, and YoK contributed to the study concept and design, acquired the data, and drafted the manuscript. KJ, KK, MI, and NN performed critical reviews of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The authors received no financial support for the research, authorship, and/or publication of this article. Ethical Approval Informed consent was obtained from the patients. References 1. Helmstaedter C, Fritz NE, Kockelmann E, et al. Positive and negative psychotropic effects of levetiracetam. Epilepsy Behav. 2008; 13:535-541. 2. Sherer M, Padilla S. A case of obsessiveness induced by levetiracetam in a patient with epilepsy, intellectual disability and pervasive developmental disorder. Ment Health Aspect Dev Disabil. 2008;11:1-4. 3. Hurtado B, Koepp MJ, Sander JW, Thompson PJ. The impact of levetiracetam on challenging behavior. Epilepsy Behav. 2006;8: 588-592. 4. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision. Washington, DC: American Psychiatric Association; 2000. 5. Scahill L, Riddle MA, McSwiggin-Hardin M, et al. Children’s Yale-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry. 1997;36:844-852. 6. Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A. 2004;101:9861-9866. 7. Rosenberg DR, Keshavan MS. A.E. Bennett Research Award. Toward a neurodevelopmental model of obsessive-compulsive disorder. Biol Psychiatry. 1998;43:623-640. 8. MacMaster FP, O’Neill J, Rosenberg DR. Brain imaging in pediatric obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 2008;47:1262-1272. 9. Rosenberg DR, Mirza Y, Russell A, et al. Reduced anterior cingulate glutamatergic concentrations in childhood OCD and major depression versus healthy controls. J Am Acad Child Adolesc Psychiatry. 2004;43:1146-1153. 10. Whiteside SP, Port JD, Deacon BJ, Abramowitz JS. A magnetic resonance spectroscopy investigation of obsessive-compulsive disorder and anxiety. Psychiatry Res. 2006;146:137-147. 11. Phillips KA, Menard W. A prospective pilot study of levetiracetam for body dysmorphic disorder. CNS Spectr. 2009;14: 252-260. 12. Wang HR, Woo YS, Bahk WM. The potential role of anticonvulsants in the treatment of obsessive-compulsive and related disorders. Psychiatry Clin Neurosci. 2014 Apr 16. doi:10.1111/pcn. 12186. [Epub ahead of print]. 13. Dinkelacker V, Dietl T, Widman G, et al. Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases. Epilepsy Behav. 2003;4: 537-547. Downloaded from jcn.sagepub.com at TOHOKU UNIVERSITY MEDICAL LIB on July 14, 2014