J Clin Neurol.  2011 Sep;7(3):128-136. 10.3988/jcn.2011.7.3.128.

Psychiatric Symptoms and Quality of Life in Patients with Drug-Refractory Epilepsy Receiving Adjunctive Levetiracetam Therapy

• Lee JJ
• Song HS
• Hwang YH
• Lee HW
• Suh CK
• Park SP

• KMID: 2287627
• DOI: http://doi.org/10.3988/jcn.2011.7.3.128

Abstract

BACKGROUND AND PURPOSE
Levetiracetam (LEV) is a new antiepileptic drug that has been found to be effective as an adjunctive therapy for uncontrolled partial seizures. However, the results of several studies suggested that LEV has negative psychotropic effects, including irritability, aggressiveness, suicidality, and mood disorders. We investigated the impact of adjunctive LEV on psychiatric symptoms and quality of life (QOL) in patients with drug-refractory epilepsy (DRE) and determined the risk factors provoking psychiatric adverse events.
METHODS
A 24-week, prospective, open-label study was conducted. At enrollment, we interviewed patients and reviewed their medical charts to collect demographic and clinical information. They were asked to complete self-report health questionnaires designed to measure various psychiatric symptoms and QOL at enrollment and 24 weeks later.
RESULTS
Seventy-one patients were included in the study, 12 patients (16.9%) of whom discontinued LEV therapy due to serious adverse events including suicidality. The risk factor for premature withdrawal was a previous history of psychiatric diseases (odds ratio 4.59; 95% confidence interval, 1.22-17.32). LEV intake resulted in significant improvements in Beck Anxiety Inventory score (p<0.01) and some domains of the Symptom Checklist-90-Revised, such as somatization (p<0.05), obsessive-compulsiveness (p<0.05), depression (p<0.05), and anxiety (p<0.05). These improvements were not related to the occurrence of seizure freedom. The Quality of Life in Epilepsy Inventory-31 overall score and subscale scores, such as seizure worry (p<0.01), overall QOL (p<0.05), emotional well-being (p<0.05), energy-fatigue (p<0.05), and social function (p<0.05), also improved.
CONCLUSIONS
Adjunctive LEV in patients with DRE is likely to improve psychiatric symptoms and QOL. Clinicians should be well aware of the psychiatric histories of patients to prevent them from developing serious adverse events related to LEV.

Keyword

drug refractory; epilepsy; levetiracetam; psychiatric symptoms; suicide; quality of life

MeSH Terms

Anxiety
Depression
Epilepsy
Freedom
Humans
Mood Disorders
Piracetam
Prospective Studies
Quality of Life
Risk Factors
Seizures
Suicide
Surveys and Questionnaires
Piracetam

Reference

1. Park SP, Song HS, Hwang YH, Lee HW, Suh CK, Kwon SH. Differential effects of seizure control and affective symptoms on quality of life in people with epilepsy. Epilepsy Behav. 2010. 18:455–459.

2. Lim HW, Song HS, Hwang YH, Lee HW, Suh CK, Park SP, et al. Predictors of suicidal ideation in people with epilepsy living in Korea. J Clin Neurol. 2010. 6:81–88.

3. Cramer JA, Blum D, Fanning K, Reed M. Epilepsy Impact Project Group. The impact of comorbid depression on health resource utilization in a community sample of people with epilepsy. Epilepsy Behav. 2004. 5:337–342.

4. Mula M, Monaco F. Antiepileptic drugs and psychopathology of epilepsy: an update. Epileptic Disord. 2009. 11:1–9.

5. Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman B. Early development of intractable epilepsy in children: a prospective study. Neurology. 2001. 56:1445–1452.

6. Nilsson L, Ahlbom A, Farahmand BY, Asberg M, Tomson T. Risk factors for suicide in epilepsy: a case control study. Epilepsia. 2002. 43:644–651.

7. Baker GA, Jacoby A, Buck D, Stalgis C, Monnet D. Quality of life of people with epilepsy: a European study. Epilepsia. 1997. 38:353–362.

8. Ketter TA, Post RM, Theodore WH. Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders. Neurology. 1999. 53:S53–S67.

9. Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology. 2000. 55:236–242.

10. Heo K, Lee BI, Yi SD, Huh K, Kim JM, Lee SA, et al. Efficacy and safety of levetiracetam as adjunctive treatment of refractory partial seizures in a multicentre open-label single-arm trial in Korean patients. Seizure. 2007. 16:402–409.

11. De Smedt T, Raedt R, Vonck K, Boon P. Levetiracetam: part II, the clinical profile of a novel anticonvulsant drug. CNS Drug Rev. 2007. 13:57–78.

12. Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, 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.

13. Muralidharan A, Bhagwagar Z. Potential of levetiracetam in mood disorders: a preliminary review. CNS Drugs. 2006. 20:969–979.

14. Cramer JA, De Rue K, Devinsky O, Edrich P, Trimble MR. A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials. Epilepsy Behav. 2003. 4:124–132.

15. Ciesielski AS, Samson S, Steinhoff BJ. Neuropsychological and psychiatric impact of add-on titration of pregabalin versus levetiracetam: a comparative short-term study. Epilepsy Behav. 2006. 9:424–431.

16. Mazza M, Martini A, Scoppetta M, Mazza S. Effect of levetiracetam on depression and anxiety in adult epileptic patients. Prog Neuropsychopharmacol Biol Psychiatry. 2008. 32:539–543.

17. Wu T, Chen CC, Chen TC, Tseng YF, Chiang CB, Hung CC, et al. Clinical efficacy and cognitive and neuropsychological effects of levetiracetam in epilepsy: an open-label multicenter study. Epilepsy Behav. 2009. 16:468–474.

18. Hurtado B, Koepp MJ, Sander JW, Thompson PJ. The impact of levetiracetam on challenging behavior. Epilepsy Behav. 2006. 8:588–592.

19. Weintraub D, Buchsbaum R, Resor SR Jr, Hirsch LJ. Psychiatric and behavioral side effects of the newer antiepileptic drugs in adults with epilepsy. Epilepsy Behav. 2007. 10:105–110.

20. Bootsma HP, Ricker L, Diepman L, Gehring J, Hulsman J, Lambrechts D, et al. Levetiracetam in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center. Epilepsy Behav. 2007. 10:296–303.

21. Mula M, Sander JW. Suicidal ideation in epilepsy and levetiracetam therapy. Epilepsy Behav. 2007. 11:130–132.

22. Mula M, Trimble MR, Sander JW. Are psychiatric adverse events of antiepileptic drugs a unique entity? A study on topiramate and levetiracetam. Epilepsia. 2007. 48:2322–2326.

23. Helmstaedter C, Fritz NE, Kockelmann E, Kosanetzky N, Elger CE. Positive and negative psychotropic effects of levetiracetam. Epilepsy Behav. 2008. 13:535–541.

24. Labiner DM, Ettinger AB, Fakhoury TA, Chung SS, Shneker B, Tatum Iv WO, et al. Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy. Epilepsia. 2009. 50:434–442.

25. de la Loge C, Hunter SJ, Schiemann J, Yang H. Assessment of behavioral and emotional functioning using standardized instruments in children and adolescents with partial-onset seizures treated with adjunctive levetiracetam in a randomized, placebo-controlled trial. Epilepsy Behav. 2010. 18:291–298.

26. Andersohn F, Schade R, Willich SN, Garbe E. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology. 2010. 75:335–340.

27. Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman B. Early development of intractable epilepsy in children: a prospective study. Neurology. 2001. 56:1445–1452.

28. Kim ZS, Lee YS, Lee MS. Two- and four-subtest short forms of the Korean-Wechsler Adult Intelligence Scale. Seoul J Psychiatry. 1994. 19:121–126.

29. Rhee MK, Lee YH, Jung HY, Choi JH, Kim SH, Kim YK, et al. A standardization study of Beck Depression Inventory (II): Korean version (K-BDI): validity. Korean J Psychopathol. 1995. 4:96–104.

30. Yook SP, Kim ZS. A clinical study on the Korean version of Beck Anxiety Inventory: comparative study of patient and non-patient. Korean J Clin Psychol. 1997. 16:185–197.

31. Kim JH, Kim KI. The standardization study of symptom checklist-90-revision in Korea III. Ment Health Res. 1984. 2:278–311.

32. Shin MS, Park KB, Oh KJ, Kim ZS. A study of suicidal ideation among high school students: the structural relation among depression, hopelessness, and suicidal ideation. Korean J Clin Psychol. 1990. 9:1–19.

33. Yoo HJ, Lee SA, Heo K, Kang JK, Ko RW, Yi SD, et al. The reliability and validity of Korean QOLIE-31 in patients with epilepsy. J Korean Epilepsy Soc. 2002. 6:45–52.

34. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1981. 22:489–501.

35. Otoul C, Arrigo C, van Rijckevorsel K, French JA. Meta-analysis and indirect comparisons of levetiracetam with other second-generation antiepileptic drugs in partial epilepsy. Clin Neuropharmacol. 2005. 28:72–78.

36. French J, Edrich P, Cramer JA. A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. Epilepsy Res. 2001. 47:77–90.

37. Arroyo S, Crawford P. Safety profile of levetiracetam. Epileptic Disord. 2003. 5:Suppl 1. S57–S63.

38. Harden C. Safety profile of levetiracetam. Epilepsia. 2001. 42:Suppl 4. 36–39.

39. Wolf P. Acute behavioral symptomatology at disappearance of epileptiform EEG abnormality. Paradoxical or "forced" normalization. Adv Neurol. 1991. 55:127–142.

40. Statistical review and evaluation: antiepileptic drugs and suicidality. 2008. 05. 23. Accessed 2009 Dec 4. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4372b1-01-FDA.pdf.

41. Birbeck GL, Hays RD, Cui X, Vickrey BG. Seizure reduction and quality of life improvements in people with epilepsy. Epilepsia. 2002. 43:535–538.

42. Schmitz B. Effects of antiepileptic drugs on mood and behavior. Epilepsia. 2006. 47:Suppl 2. 28–33.