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1 Self Reported Feelings Of Anger And Aggression Towards Others In Patients On Levetiracetam: A Cohort study using the UK Anti Epileptic Drug Register Journal: BMJ Open Manuscript ID: bmjopen-0-00 Article Type: Research Date Submitted by the Author: 0-Jan-0 Complete List of Authors: Wieshmann, Udo; The Walton Centre for Neurology and Neurosurgery, Baker, Gus; University of Liverpool, Neurosciences <b>primary Subject Heading</b>: Neurology Secondary Subject Heading: Patient-centred medicine Keywords: Epilepsy < NEUROLOGY, CLINICAL PHARMACOLOGY, Adverse events < THERAPEUTICS BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

2 Page of BMJ Open 0 0 Self Reported Feelings Of Anger And Aggression Towards Others In Patients On Levetiracetam: A Cohort study using the UK Anti Epileptic Drug Register Udo Carl Wieshmann, Gus Baker The Walton Centre for Neurology and Neurosurgery Liverpool, UK Address of corresponding author: Dr Udo C Wieshmann, The Walton Centre for Neurology and Neurosurgery, Lower Lane, Liverpool, UK Phone 0 Fax 0 udo.wieshmann@thewaltoncentre.nhs.uk or udo.wieshmann@btinternet.com Running Title: Anger And Levetiracetam - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

3 Page of 0 0 Article Summary Article focus Levetiracetam (LEV) is a new and widely used Anti Epileptic Drug. We used data from the UK Antiepileptic Drug register to study the link between LEV and anger. Key messages Forty nine percent of patients on LEV reported anger as being sometimes or always a problem. Strength and limitations Abstract Adverse effects were self reported, the register is observational. Nevertheless, our register offered insight into the adverse effects of LEV. Objectives To ascertain the frequency of self-reported anger and depression in Levetiracetam (LEV). Design We compared patients with epilepsy (PWE) taking LEV with PWE taking other Anti Epileptic Drugs (AED). Setting All PWE and controls submitted information to the UK AED register. Participants We analysed the data of PWE and control subjects. One hundred fifty eight took LEV in monotherapy or as part of polypharmacotherapy, PWE took other AED. Primary and secondary outcome measures All PWE and controls completed the Liverpool Adverse Event Profile (LAEP) which includes items on anger and depression quantified on a -point Likert scale, with indicating that there was never a problem;, rarely a problem;, sometimes a problem; and, always or often a problem. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

4 Page of BMJ Open 0 0 Results Forty nine percent of PWE on LEV and % on AED other than LEV reported anger as sometimes or always being a problem (p=0.0). Forty eight percent of PWE on LEV and % on AED other than LEV reported depression as sometimes or always being a problem (p=0.). Seven percent of control subjects reported anger as sometimes being a problem, % reported anger as never or rarely being a problem. Depression was never a problem in % of controls and rarely a problem in %. Conclusions Anger and depression were more frequently reported as a problem by PWE than by control subjects. Our observational register of self-reported symptoms suggested anger being more often a problem in patients taking LEV than in PWE taking other AED. PWE should be informed about this potential problem of LEV. Keywords: Epilepsy, Levetiracetam, adverse effects. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

5 Page of 0 0 Introduction Levetiracetam (LEV) is licensed for monotherapy and adjunctive treatment of focal seizures with or without secondary generalisation, for adjunctive therapy of myoclonic seizures in patients with juvenile myoclonic epilepsy and primary generalised tonicclonic seizures in the UK. LEV is widely used. The market share of LEV in the US measured in drug costs was % in 00 ( _Drug_Market, accessed June th 0). Overall, LEV is a good Anti Epileptic Drug (AED) compared to other AED in terms of rash risks, side effects on liver and kidney and drug interactions. Unfortunately, LEV can have psychiatric adverse effects including irritability, anger, agitation, aggressive behavior and depression. - It has been estimated on the basis of collective evidence that % of all patients will suffer psychiatric side effects but compared to our clinical experience this seemed low. Feelings of anger seemed to be a particular problem, but were often only reported on direct questioning because the patients were embarrassed. The aim of our study was to find out how many patients with epilepsy (PWE) on LEV were suffering from anger. Because doctors may under-report adverse effects we obtained the information directly from the patients using a self-referral register. Methods The UK AED Register is a prospective register to study the efficacy and adverse effects of AED. The register was established at The Walton Centre for Neurology and Neurosurgery, Liverpool in July 00. Anybody who takes AED can self-refer to the register. The register is independent from the pharmaceutical industry and has been - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

6 Page of BMJ Open 0 0 approved by the local ethic committee. For the current analysis we included all subjects with complete data sets. At the time of the analysis we had subjects; patients on LEV in monotherapy or as part of polytherapy, patients on Anti Epileptic Drugs (AED) other than LEV including Carbamazepine, Lamotrigine, Topiramate, Zonisamide, Phenytoin and Phenobarbitone, and control subjects. The control subjects were employees at The Walton Centre, students at Liverpool University or patients with single seizures or very infrequent seizures not taking AED. All the data was collected using the Liverpool Adverse Event Profile (LAEP) questionnaire, which was completed by the patients either electronically via or in paper form in the Mersey Regional Epilepsy clinic at The Walton Centre in Liverpool. The variables recorded in LAEP include self reported symptoms. It is possible to analyse the scores of individual symptoms as well as calculate overall symptom score. The Liverpool Adverse Event Profile (LAEP) includes items on anger and depression quantified on a -point Likert scale, with indicating that there was never a problem;, rarely a problem;, sometimes a problem; and, always or often a problem. The complete dataset is available on request. We also collected age, gender, epileptic syndrome, severity of epilepsy, number of seizures in the last weeks and other health problems, AED and other medication. We calculated the frequency of aggression occurring sometimes or always in patients on LEV and patients on other AED, and applied the chi squared test to test for associations of aggression with LEV. We did the same for the item depression. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

7 Page of 0 0 Results Forty nine percent of patients on LEV and % on AED other than LEV reported anger as sometimes or always being a problem (p=0.0). Forty eight percent of patients on LEV and % on AED other than LEV reported depression as sometimes or always being a problem (p=0.). In patients taking LEV <000mg a day anger was reported as sometimes or always occurring in % and in patients taking LEV >000mg a day in % (p=0.). Anger occurred in LEV monotherapy in % and polytherapy in % (p=0.). There was a trend for patients on LEV to be less likely to be seizure free than patients on other AED. Seven percent of control subjects reported anger as sometimes being a problem, % reported anger as never or rarely being a problem. Depression was never a problem in % of controls and rarely a problem in %. The clinical characteristics of the patients are shown in tab.. Discussion We found a small but statistically significant increase in self- reported anger in patients on LEV in mono and polytherapy compared to patients on other AED. About half of all patients on LEV reported anger as sometimes or always being a problem. Depression was not significantly associated with LEV. The regulatory trials suggested that LEV influenced affect. Symptoms including agitation, hostility, anxiety, apathy, emotional lability, depersonalisation and depression were reported in.% of patients taking LEV and their standard AED medication compared to.% of patients taking placebo and their standard AED medication. Regulatory trials are not ideal for determination of - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

8 Page of BMJ Open 0 0 behavioral adverse effects, as patients on antidepressants and major tranquillisers are often excluded from trials. LEV has been associated with anger. Many studies reported irritability, anger, agitation, aggressive behavior and depression in patients taking LEV -, but the incidence of these adverse effects was considered to be relatively low at %. In our study the prevalence of self-reported anger was much higher. There are a number of possible explanations; doctors may be unaware of relatively subtle mood changes, they may fail to report them or patients may be too embarrassed to spontaneously report anger. In a previous small study using the LAEP we also found a disturbingly high prevalence of self-reported adverse effects suggesting that the burden of taking AED is perhaps much higher than widely assumed by doctors. This study also showed that even in monotherapy LEV was overall not better tolerated than older AED but had a different adverse effect profile. Feelings of anger were reported as always occurring in % of patients on LEV as opposed to % on Sodium Valproate, % on Carbamazepine and % Lamotrigine, in keeping with our current study []. That anger is a particular problem in LEV has been also suggested by a randomized prospective study comparing LEV with Lamotrigine (LTG). 0 LEV is a very unusual AED with a probable unique mode of action and is arguably one of the most effective new AED. LEV has a good adverse effect profile including low liver toxicity and lack of allergic skin reactions, there are no interactions with other drugs including the anti-contraceptive pill and LEV likely to have a low teratogenic risk. - LEV will remain an important AED and will potentially even become a first line drug at least in some epileptic syndromes such as juvenile myoclonic epilepsy in women. Having said this, it is important to advise patients with epilepsy about the potential of affective - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

9 Page of 0 0 changes, in particular aggressive moods. In our un-blinded observational study we could not exclude all confounding factors. The information came from the patients directly and not as in conventional custom via a physician. Our study therefore critically relied on the truthfulness of the patients. In addition, the median dose of some drugs such as Sodium Valproate, Lamotrigine, Topiramate and Zonisamide were higher in patients on LEV than in patients not on LEV. There was also a trend for patients on LEV to be less likely seizure free (tab.). LEV was used as second (or third) line drug in those patients with more difficult to control seizures. This was likely to have introduced bias and may have affected our findings. Having said this, our data reflects current clinical practice. In the future when LEV is used as a first line drug an analysis with a large group of seizure free patients on LEV could clarify this issue. It has to be kept in mind that we have selectively chosen to analyze LEV from our data pool. It is likely that analyzing other AED would also demonstrate problems in one or more areas covered by the LAEP. In addition, the risk of adverse effects has to be carefully balanced against the risk of seizures. Patients should be encouraged to take their medication. After all, half of all patients on LEV did not report anger. Nevertheless, patients with epilepsy should be made aware of this potential problem. Acknowledgment We would like to thank Andrew Pennington and David Watling for supporting the register and Carol Chadwick for her assistance in the preparation of the - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

10 Page of BMJ Open 0 0 manuscript. Contributors UW and GB conceived the idea of the UK AED register and the study. UC was responsible for the data analysis and produced the table. The initial draft of the manuscript was prepared by UW and then reviewed and amended by GB. Funding The UKAED register has been kindly supported by an Epilepsy Action grant. Competing interests None. Ethics approval The UK AED register was approved by the Liverpool North Research Ethics Committee. Data sharing statement Data can be obtained on request. References. Abou-Khalil B. Benefit: risk assessment of levetiracetam in the treatment of partial seizures. Drug Saf 00;: 0.. Cramer JA, De Rue K, Devinsky O, et al. A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials. Epilepsy Behav 00;:.. Mula M, Trimble MR, Yuen R, et al. Psychiatric adverse events during levetiracetam therapy. Neurology 00;:0 0.. White JR, Walczak TS, Leppik J, et al. Discontinuation of levetiracetam because of behavioral side effects: a case control study. Neurology 00;:.. Barrow P, Waller P, Wise L. Comparison of hospital episodes with drug-induced disorders and spontaneously reported adverse drug reactions. Br J Clin Pharmacol 00;:-.. Gilliam FG, Fessler AJ, Baker G, et al. Systematic screening allows reduction of - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

11 Page 0 of 0 0 adverse antiepileptic drug effects: a randomized trial. Neurology 00;:-.. French J, Edrich P, Cramer JA. A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. Epilepsy Res 00;: -0.. Helmstaedter C, Fritz NE, Kockelmann E, et al. Positive and negative psychotropic effects of levetiracetam. Epilepsy Behav 00;:-.. Wieshmann UC, Tan GM, Baker G. Self-reported symptoms in patients on antiepileptic drugs in monotherapy. Acta Neurol Scand 0;:-. 0. Labiner DM, Ettinger AB, Fakhoury TA, et al. Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy. Epilepsia 00;:.. Shorvon SD, van Rijckevorsel K. A new antiepileptic drug. J NeurolNeurosurg Psychiatry 00;:.. Nicolson A, Lewis SA, Smith DF. A prospective analysis of the outcome of levetiracetam in clinical practice. Neurology 00;:-0.. Hunt S, Craig J, Russell A, et al. Levetiracetam in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 00;: BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

12 Page of BMJ Open 0 0 Table LEV n= nolev n= median dose 000mg/day Gender (f/m) / / Age (mean (SD) [years]).(.).0 (.) Epilepsy (partial/generalized) / 0/ Seizure control (seizure free/seizures) 0/ / (ns) Monotherapy AED or more AED Adjunctive AED (median dose [mg/day]) Carbamazepine (00) (00) Sodium Valproate (0) (00) Lamotrigine (0) (0) Phenytoin (0) (0) Clobazam (0) (0) Topiramate 0 (0) (00) Zonisamide (0) (0) Primidone () () Gabapentin (0) (00) Lacosamide (0) () Phenobarbitone (0) () Clonazepam (.) (0.) OTHER* *Other drugs were Rufinamide, Pregabalin, Escitalopram, Diazepam, Nitrazepam, Lorazepam, Piracetam, Ethosuximide, Acetazolamide. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

13 Page of 0 0 STROBE Statement Checklist of items that should be included in reports of cohort studies Item No Recommendation Title and abstract (a) Indicate the study s design with a commonly used term in the title or the abstract (b) Provide in the abstract an informative and balanced summary of what was done and what was found Introduction Background/rationale Explain the scientific background and rationale for the investigation being reported Objectives State specific objectives, including any prespecified hypotheses Methods Study design Present key elements of study design early in the paper Setting Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection Participants (a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up (b) For matched studies, give matching criteria and number of exposed and unexposed Variables Clearly define all outcomes, exposures, predictors, potential confounders, and effect Data sources/ measurement modifiers. Give diagnostic criteria, if applicable * For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group Bias Describe any efforts to address potential sources of bias Study size 0 Explain how the study size was arrived at Quantitative variables Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why Statistical methods (a) Describe all statistical methods, including those used to control for confounding (b) Describe any methods used to examine subgroups and interactions (c) Explain how missing data were addressed (d) If applicable, explain how loss to follow-up was addressed (e) Describe any sensitivity analyses Results Participants * (a) Report numbers of individuals at each stage of study eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed (b) Give reasons for non-participation at each stage (c) Consider use of a flow diagram Descriptive data * (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders (b) Indicate number of participants with missing data for each variable of interest (c) Summarise follow-up time (eg, average and total amount) Outcome data * Report numbers of outcome events or summary measures over time Main results (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, % confidence interval). Make clear which confounders were adjusted for and why they were included (b) Report category boundaries when continuous variables were categorized (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period Other analyses Report other analyses done eg analyses of subgroups and interactions, and sensitivity analyses Discussion Key results Summarise key results with reference to study objectives Limitations Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias Interpretation 0 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence Generalisability Discuss the generalisability (external validity) of the study results Other information Funding Give the source of funding and the role of the funders for the present study and, if - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

14 Page of BMJ Open 0 0 applicable, for the original study on which the present article is based *Give information separately for exposed and unexposed groups. Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at Annals of Internal Medicine at and Epidemiology at Information on the STROBE Initiative is available at BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

15 Self Reported Feelings Of Anger And Aggression Towards Others In Patients On Levetiracetam: Data from the UK Anti Epileptic Drug Register Journal: BMJ Open Manuscript ID: bmjopen-0-00.r Article Type: Research Date Submitted by the Author: -Feb-0 Complete List of Authors: Wieshmann, Udo; The Walton Centre for Neurology and Neurosurgery, Baker, Gus; University of Liverpool, Neurosciences <b>primary Subject Heading</b>: Neurology Secondary Subject Heading: Patient-centred medicine, Pharmacology and therapeutics Keywords: Epilepsy < NEUROLOGY, CLINICAL PHARMACOLOGY, Adverse events < THERAPEUTICS Note: The following files were submitted by the author for peer review, but cannot be converted to PDF. You must view these files (e.g. movies) online. lev&angerr.doc BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

16 Page of BMJ Open 0 0 Self Reported Feelings Of Anger And Aggression Towards Others In Patients On Levetiracetam: Data from the UK Anti Epileptic Drug Register Udo Carl Wieshmann, Gus Baker The Walton Centre for Neurology and Neurosurgery Liverpool, UK Address of corresponding author: Dr Udo C Wieshmann, The Walton Centre for Neurology and Neurosurgery, Lower Lane, Liverpool, UK Phone 0 Fax 0 udo.wieshmann@thewaltoncentre.nhs.uk or udo.wieshmann@btinternet.com Running Title: Anger And Levetiracetam - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

17 Page of 0 0 Article Summary Article focus Key messages Levetiracetam (LEV) is a new and widely used Anti Epileptic Drug. We used data from the UK Antiepileptic Drug register to study the link between LEV and anger. Forty nine percent of patients on LEV reported anger as being sometimes or always a problem. Strength and limitations Abstract Adverse effects were self reported, the register is observational. Nevertheless, our register offered insight into the adverse effects of LEV. Objectives To ascertain the frequency of self-reported anger and depression in Levetiracetam (LEV). Design We compared patients with epilepsy (PWE) taking LEV with PWE taking other Anti Epileptic Drugs (AED). Setting All PWE and controls submitted information to the UK AED register. Participants We analyzed the data of PWE and control subjects. One hundred fifty eight took LEV in monotherapy or as part of polypharmacotherapy, PWE took other AED. Primary and secondary outcome measures All PWE and controls completed the Liverpool Adverse Event Profile (LAEP) which includes items on anger and depression quantified on a -point Likert scale, with indicating that there was never a problem;, rarely a problem;, sometimes a problem; and, always or often a problem. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

18 Page of BMJ Open 0 0 Results Forty nine percent of PWE on LEV and % on AED other than LEV reported anger as sometimes or always being a problem (p=0.0). Forty eight percent of PWE on LEV and % on AED other than LEV reported depression as sometimes or always being a problem (p=0.). Seven percent of control subjects reported anger as sometimes being a problem, % reported anger as never or rarely being a problem. Depression was never a problem in % of controls and rarely a problem in %. Conclusions Anger and depression were more frequently reported as a problem by PWE than by control subjects. Our observational register of self-reported symptoms suggested anger being more often a problem in patients taking LEV than in PWE taking other AED. PWE should be informed about this potential problem of LEV. Keywords: Epilepsy, Levetiracetam, adverse effects. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

19 Page of 0 0 Introduction Levetiracetam (LEV) is licensed for monotherapy and adjunctive treatment of focal seizures with or without secondary generalisation, for adjunctive therapy of myoclonic seizures in patients with juvenile myoclonic epilepsy and primary generalised tonic-clonic seizures in the UK. LEV is widely used. The market share of LEV in the US measured in drug costs was % in 00 ( _Drug_Market, accessed June th 0). Overall, LEV is a good Anti Epileptic Drug (AED) compared to other AED in terms of rash risks, side effects on liver and kidney and drug interactions. Unfortunately, LEV can have psychiatric adverse effects including irritability, anger, agitation, aggressive behavior and depression. - It has been estimated on the basis of collective evidence that % of all patients will suffer psychiatric side effects but compared to our clinical experience this seemed low. Feelings of anger seemed to be a particular problem, but were often only reported on direct questioning because the patients were embarrassed. The aim of our study was to find out how many patients with epilepsy (PWE) on LEV were suffering from anger. Because doctors may under-report adverse effects we obtained the information directly from the patients using a self-referral register. Methods The UK AED Register is a prospective register to study the efficacy and adverse effects of AED. The register was established at The Walton Centre for Neurology and Neurosurgery, Liverpool in July 00. Anybody who takes AED can self-refer to the register. The register is independent from the pharmaceutical industry. The register has - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

20 Page of BMJ Open 0 0 been approved by the Liverpool North Reginal Ethics committee. For the current analysis we included all subjects with complete data sets. At the time of the analysis we had subjects; patients on LEV in monotherapy or as part of polytherapy, patients on Anti Epileptic Drugs (AED) other than LEV including Carbamazepine, Lamotrigine, Topiramate, Zonisamide, Phenytoin and Phenobarbitone, and control subjects. The control subjects were employees at The Walton Centre, students at Liverpool University or patients with single seizures or very infrequent seizures not taking AED. All the data was collected using the Liverpool Adverse Event Profile (LAEP) questionnaire, which was completed by the patients either electronically via or in paper form in the Mersey Regional Epilepsy clinic at The Walton Centre in Liverpool. The variables recorded in LAEP include self reported symptoms. It is possible to analyse the scores of individual symptoms as well as calculate overall symptom score. The Liverpool Adverse Event Profile (LAEP) includes items on anger and depression quantified on a -point Likert scale, with indicating that there was never a problem;, rarely a problem;, sometimes a problem; and, always or often a problem. The complete dataset is available on request. We also collected age, gender, epileptic syndrome, severity of epilepsy, number of seizures in the last weeks and other health problems, AED and other medication. We calculated the frequency of aggression occurring sometimes or always in patients on LEV and patients on other AED, and applied the chi squared test to test for associations of aggression with LEV. We did the same for the item depression. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

21 Page of 0 0 Results Forty nine percent of patients on LEV and % on AED other than LEV reported anger as sometimes or always being a problem (p=0.0). Forty eight percent of patients on LEV and % on AED other than LEV reported depression as sometimes or always being a problem (p=0.). In patients taking LEV <000mg a day anger was reported as sometimes or always occurring in % and in patients taking LEV >000mg a day in % (p=0.). Anger occurred in LEV monotherapy in % and polytherapy in % (p=0.). There was a trend for patients on LEV to be less likely to be seizure free than patients on other AED. Seven percent of control subjects reported anger as sometimes being a problem, % reported anger as never or rarely being a problem. Depression was never a problem in % of controls and rarely a problem in %. The clinical characteristics of the patients are shown in tab.. Discussion We found a small but statistically significant increase in self- reported anger in patients on LEV in mono and polytherapy compared to patients on other AED. About half of all patients on LEV reported anger as sometimes or always being a problem. Depression was not significantly associated with LEV. The regulatory trials suggested that LEV influenced affect. Symptoms including agitation, hostility, anxiety, apathy, emotional lability, depersonalisation and depression were reported in.% of patients taking LEV and their standard AED medication compared to.% of patients taking placebo and their - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

22 Page of BMJ Open 0 0 standard AED medication. Regulatory trials are not ideal for determination of behavioral adverse effects, as patients on antidepressants and major tranquillisers are often excluded from trials. LEV has been associated with anger. Many studies reported irritability, anger, agitation, aggressive behavior and depression in patients taking LEV -, but the incidence of these adverse effects was considered to be relatively low at %. study the prevalence of self-reported anger was much higher. There are a number of In our possible explanations; doctors may be unaware of relatively subtle mood changes, they may fail to report them or patients may be too embarrassed to spontaneously report anger. In a previous small study using the LAEP we also found a disturbingly high prevalence of self-reported adverse effects suggesting that the burden of taking AED is perhaps much higher than widely assumed by doctors. This study also showed that even in monotherapy LEV was overall not better tolerated than older AED but had a different adverse effect profile. Feelings of anger were reported as always occurring in % of patients on LEV as opposed to % on Sodium Valproate, % on Carbamazepine and % Lamotrigine, in keeping with our current study []. That anger is a particular problem in LEV has been also suggested by a randomized prospective study comparing LEV with Lamotrigine (LTG). 0 LEV is a very unusual AED with a probable unique mode of action and is arguably one of the most effective new AED. LEV has a good adverse effect profile. There is low liver toxicity and lack of allergic skin reactions. LEV is likely to have a low teratogenic risk. In addition, LEV has no interactions with the anti-contraceptive pill - LEV will remain an important AED and will potentially even become a first line drug in some epileptic syndromes such as juvenile myoclonic epilepsy in women. Having said this, it is - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

23 Page of 0 0 important to advise patients with epilepsy about the potential of affective changes, in particular aggressive moods. In our un-blinded observational study on the effects of LEV on mood we could not exclude all confounding factors. The information came from the patients directly and not as in conventional custom via a physician. Our study therefore critically relied on the truthfulness of the patients. In addition, the median dose of some drugs such as Sodium Valproate, Lamotrigine, Topiramate and Zonisamide were higher in patients on LEV than in patients not on LEV. There was also a trend for patients on LEV to be less likely seizure free (tab.). LEV was used as second (or third) line drug in those patients with more difficult to control seizures. This was likely to have introduced bias and may have affected our findings. Having said this, our data reflected current clinical practice. There are a number of unanswered questions which could be addressed in future studies. These include the effect of LEV on affect in mono therapy inpatients with relatively mild epilepsy, the effect of LEV on anger in patients with symptomatic epilepsy and hippocampal sclerosis (HS) and the effect of LEV on anger in patients who take LEV and Topiramate or Zonisamide. It has to be kept in mind that we have selectively chosen to analyze LEV from our data pool. It is likely that analyzing other AED would also demonstrate problems in one or more areas covered by the LAEP. In addition, the risk of adverse effects has to be carefully balanced against the risk of seizures. Patients should be encouraged to take their medication. After all, half of all patients on LEV did not report anger. Nevertheless, patients with epilepsy should be made aware of this potential problem. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

24 Page of BMJ Open 0 0 Acknowledgment We would like to thank Andrew Pennington and David Watling for supporting the register and Carol Chadwick for her assistance in the preparation of the manuscript. Contributors UW and GB conceived the idea of the UK AED register and the study. UC was responsible for the data analysis and produced the table. The initial draft of the manuscript was prepared by UW and then reviewed and amended by GB. Funding The UKAED register has been kindly supported by an Epilepsy Action grant. Competing interests None. Ethics approval The UK AED register was approved by the Liverpool North Research Ethics Committee. Data sharing statement Data can be obtained on request. References. Abou-Khalil B. Benefit: risk assessment of levetiracetam in the treatment of partial seizures. Drug Saf 00;: 0.. Cramer JA, De Rue K, Devinsky O, et al. A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials. Epilepsy Behav 00;:.. Mula M, Trimble MR, Yuen R, et al. Psychiatric adverse events during levetiracetam therapy. Neurology 00;:0 0.. White JR, Walczak TS, Leppik J, et al. Discontinuation of levetiracetam because of behavioral side effects: a case control study. Neurology 00;:. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

25 Page 0 of 0 0. Barrow P, Waller P, Wise L. Comparison of hospital episodes with drug-induced disorders and spontaneously reported adverse drug reactions. Br J Clin Pharmacol 00;:-.. Gilliam FG, Fessler AJ, Baker G, et al. Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial. Neurology 00;:-.. French J, Edrich P, Cramer JA. A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. Epilepsy Res 00;: -0.. Helmstaedter C, Fritz NE, Kockelmann E, et al. Positive and negative psychotropic effects of levetiracetam. Epilepsy Behav 00;:-.. Wieshmann UC, Tan GM, Baker G. Self-reported symptoms in patients on antiepileptic drugs in monotherapy. Acta Neurol Scand 0;:-. 0. Labiner DM, Ettinger AB, Fakhoury TA, et al. Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy. Epilepsia 00;:.. Shorvon SD, van Rijckevorsel K. A new antiepileptic drug. J NeurolNeurosurg Psychiatry 00;:.. Nicolson A, Lewis SA, Smith DF. A prospective analysis of the outcome of levetiracetam in clinical practice. Neurology 00;:-0.. Hunt S, Craig J, Russell A, et al. Levetiracetam in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 00;: BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

26 Page of BMJ Open BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

27 Page of 0 0 Table LEV n= nolev n= median dose 000mg/day Gender (f/m) / / Age (mean (SD) [years]).(.).0 (.) Epilepsy (partial/generalised) / 0/ Seizure control (seizure free/seizures) 0/ / (ns) Monotherapy AED or more AED Adjunctive AED (median dose [mg/day]) Carbamazepine (00) (00) Sodium Valproate (0) (00) Lamotrigine (0) (0) Phenytoin (0) (0) Clobazam (0) (0) Topiramate 0 (0) (00) Zonisamide (0) (0) Primidone () () Gabapentin (0) (00) Lacosamide (0) () Phenobarbitone (0) () Clonazepam (.) (0.) OTHER* *Other drugs were Rufinamide, Pregabalin, Escitalopram, Diazepam, Nitrazepam, Lorazepam, Piracetam, Ethosuximide, Acetazolamide. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

28 Page of BMJ Open 0 0 STROBE Statement Checklist of items that should be included in reports of cohort studies Item No Recommendation Title and abstract (a) Indicate the study s design with a commonly used term in the title or the abstract (b) Provide in the abstract an informative and balanced summary of what was done and what was found Introduction Background/rationale Explain the scientific background and rationale for the investigation being reported Objectives State specific objectives, including any prespecified hypotheses Methods Study design Present key elements of study design early in the paper Setting Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection Participants (a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up (b) For matched studies, give matching criteria and number of exposed and unexposed Variables Clearly define all outcomes, exposures, predictors, potential confounders, and effect Data sources/ measurement modifiers. Give diagnostic criteria, if applicable * For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group Bias Describe any efforts to address potential sources of bias Study size 0 Explain how the study size was arrived at Quantitative variables Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why Statistical methods (a) Describe all statistical methods, including those used to control for confounding (b) Describe any methods used to examine subgroups and interactions (c) Explain how missing data were addressed (d) If applicable, explain how loss to follow-up was addressed (e) Describe any sensitivity analyses Results Participants * (a) Report numbers of individuals at each stage of study eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed (b) Give reasons for non-participation at each stage (c) Consider use of a flow diagram Descriptive data * (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders (b) Indicate number of participants with missing data for each variable of interest (c) Summarise follow-up time (eg, average and total amount) Outcome data * Report numbers of outcome events or summary measures over time Main results (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, % confidence interval). Make clear which confounders were adjusted for and why they were included (b) Report category boundaries when continuous variables were categorized (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period Other analyses Report other analyses done eg analyses of subgroups and interactions, and sensitivity analyses Discussion Key results Summarise key results with reference to study objectives Limitations Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias Interpretation 0 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence Generalisability Discuss the generalisability (external validity) of the study results Other information Funding Give the source of funding and the role of the funders for the present study and, if - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.

29 Page of 0 0 applicable, for the original study on which the present article is based *Give information separately for exposed and unexposed groups. Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at Annals of Internal Medicine at and Epidemiology at Information on the STROBE Initiative is available at BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on December 0 by guest. Protected by copyright.