Antiepileptics for aggression and associated impulsivity
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
This review aims to evaluate the efficacy of antiepileptic drugs in reducing aggression and associated impulsivity.
Background
Description of the condition
The term aggression has been used to define a broad range of behaviours, which generally involve non‐accidental harm. This includes violence, defined by the World Health Organisation as ‘the intentional use of physical force or power, threatened or actual, against oneself, another person, or against a group or community, that either results in or has a high likelihood of resulting in injury, death or psychological harm, maldevelopment or deprivation.’ Worldwide, violence is considered to be a major public health issue (World Health Organization 2002), and survey data on criminal violence in the UK has revealed that in the year 2006/7 there were just under 2½ million violent crimes in private households. Aggression is also used to describe other disturbed behaviour, such as intentional damage to property or hostile agitation.
Two broad subtypes of aggression have been identified; instrumental and reactive (Barratt 1999; Berkowitz 1993; Vitiello 1997). Instrumental aggression is more controlled and consciously goal‐directed. Reactive aggression, which is considered to be far more prevalent (Nelson 2007), involves an emotionally driven reaction to frustration or perceived threat. A key feature of reactive aggression is impulsivity. Impulsivity describes a tendency to act on impulse, i.e. a sudden or involuntary inclination or tendency to act without premeditation or reflection.
There is a well established link between mental disorder and aggression. Aggressive behaviour is an integral part of some disorders. It should be noted that the conventional diagnostic systems, ICD 10 and DSM IV, have been shaped by the medical model that relies on the identification of symptoms to determine pathology. However, mental disorder diagnoses, especially those associated with aggression, give undue prominence to behaviours rather than underlying process disturbances. Consequently there is the tautological problem that the diagnostic criteria are used both to identify the disorder and to characterise the disorder. However many mental disorders including antisocial personality disorder and conduct disorder appear to be aetiologically heterogeneous rather than distinct unitary phenomena. In the case of ‘intermittent explosive disorder’, extreme aggression is the defining feature. In this condition there is failure to resist aggressive impulses with a disproportionate response to stress (DSM‐IV‐TR; American Psychiatric Association 2000). A study of psychiatric out‐patients found the life‐time prevalence of intermittent explosive disorder to be 7.3% (Kessler 2006).
A history of aggression can contribute to the diagnosis of certain personality disorders. A ‘very low tolerance to frustration and a low threshold for discharge of aggression’ is a diagnostic feature of dissocial personality disorder under ICD‐10 (World Health Organization 1993). The broader category of antisocial personality disorder within DSM‐IV includes the criterion ‘irritability and aggressiveness as indicated by repeated physical fights or assaults’. Key features of borderline personality disorder under DSM‐IV are emotional dysregulation and impulsivity, which may be manifest in ‘inappropriate, intense anger or difficulty controlling anger (e.g. frequent displays of temper, constant anger, recurrent physical fights)’. The ICD‐10 equivalent, ‘emotionally unstable personality disorder’, refers to ‘liability to outbursts of anger or violence’. Impulsivity is also a diagnostic criterion in these two personality disorders.
Certain developmental disorders may also present with aggressive behaviour. Two of the four conduct disorder symptom clusters involve aggression (DSM‐IV‐TR). The ‘aggression to people and animals’ cluster include items such as ‘often initiates fights’, ‘has used a weapon’ and ‘has been physically cruel to people’. There is also a ‘destruction of property’ cluster which includes ‘has deliberately destroyed others’ property’. Oppositional defiant disorder is characterised by ‘a pattern of negativistic, hostile and defiant behaviour’ (DSM‐IV‐TR).
There are other mental disorders which do not have aggression as a specific diagnostic criterion, but which have been found to be associated with an increased risk of aggression. Substance abuse disorders are strongly associated with aggression (Nestor 2002). Epidemiological studies have established a modest but significant relationship between psychosis and violence (Brennan 2000; Arseneault 2000; Fazel 2006). In the developmental period, attention‐deficit hyperactivity disorder, which involves a loss of impulse control, is associated with aggression (Staller 2007). Across mental disorders, key traits that are associated with aggression are impulse control and affect regulation (Nestor 2002).
It has long been recognised that aggression can be a feature of organic brain conditions (Haller 2006). Aggressiveness may be specifically associated with frontal and temporal lobe damage (Anderson 1999; Hawkins 2000). A diagnostic criterion of organic personality disorder is ‘irritability and/or outbursts of anger and aggression’ (World Health Organization 1993). A specific relationship between epilepsy and aggression has also been found in adults (Kanemoto 1999; van Elst 2000) and children (Connor 1996).
Description of the intervention
The use of antiepileptic drugs in the treatment of aggression has a relatively long track‐record (e.g. Tyrer 1988; Stein 1992) and there are some supporting data (Goedhard 2006). Using a double‐blind crossover design phenytoin has been shown to be associated with a reduction in the frequency of acts of aggression by individuals in a community sample (Stanford 2001) and in a prison sample (Barratt 1997). A similar effect has been found with carbamazepine and sodium valproate (Gardner 1986; Kavoussi 1989; Lindermayer 2000). The effect may be specific to impulsive aggression as opposed to instrumental aggression (Barratt 1997; Stanford 2001). There is some empirical support for the anti‐aggression effect of other antiepileptics, such as divalproex (Hollander 2003; Hollander 2005), lamotrigine (Tritt 2005) and topiramate (Gobbi 2006).
An antiepileptic drug is defined here as one normally used prophylactically to reduce the frequency and/or severity of epileptic seizures. We will consider pharmacological interventions where an antiepileptic drug is given not only as monotherapy but also as an adjunctive intervention. The review will focus on studies of persistent/serious aggression. We will include, but not confine ourselves, to studies of individuals resistant to other interventions.
How the intervention might work
Impulsive reactive aggression reflects a high arousal state (Haller 2006; Nelson 2007). It has been proposed that repeated acts of aggression, specifically of a reactive sort, may be underpinned by neuronal hyperexcitability, and there is some empirical support for this (Keele 2005). Therefore drugs which reduce neuronal excitability, and specifically those classed as antiepileptics or anticonvulsants, could theoretically be expected to lower the likelihood of reactive aggressive outburst.
The precise mechanisms by which this occurs are not fully understood. At a neurochemical level, an imbalance of gabaminergic systems is thought to be associated with aggression (Nelson 2007; Siever 2008), and gamma‐aminobutyric acid (GABA) has been found to suppress aggression in animal models (Miczek 2002). Therefore it follows that pharmacological antiepileptic agents that act on gabaminergic neurons, such as carbamazepine, phenytoin and valproate, may have a beneficial effect on aggressive behaviour.
Why it is important to do this review
Poorly controlled aggression is prevalent in society. It results in emotional and physical damage to victims, and is associated with considerable costs and distress. Medication has potential to provide one treatment option, and may be particularly relevant to individuals who seek treatment but who find difficulty engaging in psychological interventions. There is some evidence that antiepileptic drugs may be effective, but there are currently no clinical guidelines. A systematic review of the current evidence base is therefore timely.
Objectives
This review aims to evaluate the efficacy of antiepileptic drugs in reducing aggression and associated impulsivity.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials in which participants have been randomly allocated to an experimental group and a control group.
Types of participants
Individuals of any age, of either sex, from any cultural background, and in any setting who have displayed recurrent aggression as defined by the authors of the study. We will include participants diagnosed with a mental illness, personality disorder, impulse disorder, or who have received a brain injury, but will exclude people with dementia. We will include studies where antiepileptics are used to treat people with epilepsy, but only if they have also displayed recurrent aggression.
Types of interventions
Any antiepileptic drug (including all antiepileptic drugs listed in Section 4.8 of the British National Formulary) in any dosage, used for any length of time, and measured against a placebo.
For the purpose if this review, an antiepileptic drug is defined as one used prophylactically to reduce the frequency and/or severity of epileptic seizures. Drugs used in the acute treatment of status epilepticus but which are not generally prescribed for the prophylaxis of epileptic seizures (such as chlormethiazole, diazepam, fosphenytoin, lorazepam, midazolam, paraldehyde) are excluded. We will not include studies where antiepileptic drugs are used to treat acute presentations, as in rapid tranquillisation procedures.
We will include studies where the antiepileptic drug being evaluated is given as an adjunct to another drug not classed as an antiepileptic or as an adjunct to a psychological intervention. Comparisons might therefore include:
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Antiepileptic versus placebo
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Antiepileptic plus other drug treatment versus placebo plus other drug treatment
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Antiepileptic plus psychological treatment versus placebo plus psychological treatment
Types of outcome measures
A number of validated instruments have been developed for the measurement of aggression. To date, however, no single measure has been identified as a superior and we therefore anticipate finding a range of outcome measures in studies identified for inclusion in this review.
Primary outcomes
(a) Primary outcomes
1. Aggression (self‐reported): reduction in aggressive behaviour or aggressive feelings; continuous outcome, measured through improvement in scores on the Aggression Questionnaire (AQ; Buss 1992), the Positive and Negative Syndrome Scale (PANSS; Kay 1989) or similar validated instrument.
2. Aggression (observer‐reported): reduction in aggressive behaviour; continuous outcome, measured through improvement in scores on the Modified Overt Aggression Scale (MOAS; Malone 1994) or the Overt Aggression Scale‐Modified (OAS‐M, Coccaro 1991) or similar validated instrument; or as number of observed incidents.
Secondary outcomes
(b) Secondary outcomes
1. Impulsivity: self‐reported improvement in impulsivity; continuous outcome, measured through reduction in scores on the Barratt Impulsivity Scale (BIS: Patton 1995) or similar validated instrument.
2. Hostility: improvement in hostility; continuous outcome, measured through reduction in scores on the hostility subscale of the observer‐reported Brief Psychiatric Rating Scale, on the hostility subscale of the self‐reported SCL‐90 (Derogartis 1973) or using a similar validated instrument.
3. Anger: self‐reported improvement in anger expression and control; continuous outcome, measured through reduction in scores on the State‐Trait Anger Expression Inventory‐2 (STAXI‐II; Spielberger 1999) or similar validated instrument.
4. Quality of life: self‐reported improvement in overall quality of life; continuous outcome, measured through improvement in scores on the European quality of life instrument (EuroQol (EuroQoL group 1990)) or similar validated instrument.
5. Satisfaction with care: continuous outcome; measured through improvement in scores on the Client Satisfaction Questionnaire (CSQ‐8; Attkisson 1982) or similar validated instrument.
6. Non‐compliance: measured as proportion of participants discontinuing treatment; continuous
7. Adverse events: measured as incidence of overall adverse events and of the three most common adverse events; dichotomous outcome, measured as numbers reporting.
Outcomes will be divided into short term (within one month), medium term (between one month and six months) and long term (between six and twelve months).
Search methods for identification of studies
Electronic searches
The following electronic databases will be searched:
‐ Cochrane Central Register of Controlled Trials (CENTRAL)
‐ MEDLINE
‐ EMBASE
‐ CINAHL
‐ CENTRAL (the most recent edition of the Cochrane Controlled Trials Register)
‐ PsycINFO
‐ Cochrane Schizophrenia Group's register of trials on aggression
‐ metaRegister of Controlled Trials
The search terms for MEDLINE will be as follows:
(exp Homicide/ OR homicid$.tw. OR murder$.tw. OR manslaughter$.tw. OR infanticid$.tw. OR parricid$.tw. OR Torture/ OR tortur$.tw. OR (intent$ adj3 (kill$ or harm$)).tw. OR (bodily adj3 (harm or assault$)).tw. OR assail$.tw. OR attacker$.tw. OR child abuse/ or spouse abuse/ OR (physical adj3 abus$).tw. OR (spous$ adj3 abus$).tw. OR (partner adj3 abus$).tw. OR (child$ adj3 neglect$).tw. OR (child$ adj3 abus$).tw. OR (elder$ adj3 abus$).tw. OR Rape/ OR (rape$ or rapist$).tw. OR (sexual$ adj3 abus$).tw. OR bugger$.tw. OR Sex Offenses/ OR sodom$.tw. OR molest$.tw. OR (pedophil$ or paedophil$).tw. OR indecen$.tw. OR (masturbat$ adj3 public).tw. OR exhibitionis$.tw. OR lewd$.tw. OR sadis$.tw. OR sadomasochis$.tw. OR abduct$.tw. OR kidnap$.tw. OR aggress$.tw. OR violen$.tw. OR exp Anger/ OR malic$.tw. OR hostil$.tw. OR ((dangerous$ or disrupt$) adj3 (behav$ or histor$ or conduct$)).tw. OR ((destruct$ not self‐destruct$) adj3 (behav$ or histor$ or conduct$)).tw. OR cruel$.tw. OR delinquen$.tw. OR threaten$.tw. OR disorderly.tw. OR affray$.tw. OR (breach$ adj3 peace).tw. OR felon$.tw. OR unlawful$.tw. OR penal$.tw. OR penol$.tw. OR Crime/ OR crim$.tw. OR offen$.tw. OR Prisons/ OR prison$.tw. OR inmate$.tw. OR correctional$.tw. OR firearm$.tw. OR weapon$.tw. OR Firearms/ OR (gun or guns).tw. OR (agitat$ not (cancer or carcinoma)).tw. OR Impulsive Behavior/ OR impulsiv$.tw.)
AND
(Anticonvulsants/ OR (epilep$ adj3 drug$).tw. OR anti‐epileptic$.tw. OR antiepileptic$.tw. OR anti‐convulsant.tw. OR anticonvulsant$.tw. OR Carbamazepine/ OR carbamazepine.tw. OR Valproic Acid/ OR (sodium adj valporate).tw. OR gabapentin.tw. OR lamotrigine.tw. OR topiramate.tw. OR ethosuxamide.tw. OR Primidone/ OR primidone.tw. OR Vigabatrin/ OR vigabatrin.tw. OR Phenobarbital/ OR (phenobarbital or phenobarbitone).tw. OR Piracetam/ OR piracetam.tw. OR Acetazolamide/ OR acetazolamide.tw. OR levetiracetam.tw. OR pregabalin.tw. OR oxcarbazepine.tw. OR tiagabine.tw. OR zonisamide.tw. OR clobazam.tw. OR Clonazepam/ OR clonazepam.tw.)
MEDLINE will be searched in combination with the Cochrane Collaboration’s search strategy for identifying reports of controlled trials as detailed in Section 6.4.11 of the Cochrane Reviewers Handbook (Higgins 2008).
Similar strategies to identify participants, antiepileptic drugs and controlled trials will be developed for the other databases.
Searching other resources
We will hand‐search the reference lists of included and excluded studies for additional relevant trials. We will also examine bibliographies of systematic review articles published in the last five years to identify relevant studies.
We will contact authors of relevant studies to enquire about other sources of information and the first author of each included study for information regarding unpublished data. Pharmaceutical companies will be contacted to request information about any published/unpublished trials using antiepileptics in the treatment of people with recurrent aggression.
Data collection and analysis
Selection of studies
Titles and abstracts will be identified, read and reviewed independently by two reviewers (NH & MF) against the inclusion criteria. Full copies of studies which appear to meet the inclusion criteria will be assessed by two independent reviewers. Uncertainties concerning the appropriateness of studies for inclusion in the review will be resolved through consultation with a third reviewer (RN). Reviewers will not be blinded to the name(s) of the study author(s), their institution(s) or publication sources at any stage of the review.
Data extraction and management
Data will be extracted independently by two reviewers (NH & MF) using a data extraction form. Data will be entered into RevMan 5. Where data are not available in the published trial reports, we will contact the authors and ask them to supply the missing information.
Assessment of risk of bias in included studies
Assessment of risk of bias in included studies
For each included study, two reviewers (NH & MF) will independently complete the Cochrane Collaboration’s tool for assessing risk of bias (Higgins 2008, section 8.5.1). Any disagreement will be resolved through consultation with a third reviewer (RN). We will assess the degree to which:
· the allocation sequence was adequately generated (‘sequence generation’)
· the allocation was adequately concealed (‘allocation concealment’)
· knowledge of the allocated interventions was adequately prevented during the study (‘blinding’)
· incomplete outcome data were adequately addressed
· reports of the study were free of suggestion of selective outcome reporting
· the study was apparently free of other problems that could put it at high risk of bias
Each domain will be allocated one of three possible categories for each of the included studies: ‘Yes’ for low risk of bias, ‘No’ for high risk of bias, and ‘Unclear’ where the risk of bias is uncertain or unknown.
Measures of treatment effect
For dichotomous (binary) data, the odds ratio with a 95% confidence interval will be used to summarise results within each study. The odds ratio is chosen because it has statistical advantages relating to its sampling distribution and its suitability for modelling, and is a relative measure so can be used to combine studies. For continuous data, such as the measurement of impulsiveness and aggression on a scale, the mean score for each outcome as determined by a standardised tool will be compared between the two groups to give a mean difference (MD), again with a 95% confidence interval. Where possible, these comparisons will be made at specific follow‐up periods: (1) within the first month, (2) between one and six months, and (3) between six and twelve months. Where possible, endpoint data will be presented. Where both endpoint and change data are available for the same outcomes, then only the former will be reported.
Continuous data that are skewed will be reported in a separate table, and treatment effect sizes will not be calculated to minimise the risk of applying parametric statistics to data that departs significantly from a normal distribution. We will define skewness as occurring when, for a scale or measure with positive values and a minimum value of zero, the mean is less than twice the standard deviation (Altman 1996).
We will use the weighted mean difference (WMD) where the same outcome measures are reported in more than one study. The standardised mean difference (SMD) will be used where different outcome measures of the same construct are reported.
Unit of analysis issues
(a) Cluster‐randomised trials
Where trials have used clustered randomization, we anticipate that study investigators would have presented their results after appropriately controlling for clustering effects (robust standard errors or hierarchical linear models). If it is unclear whether a cluster‐randomized trial has used appropriate controls for clustering, the study investigators will be contacted for further information. Where appropriate controls were not used, individual participant data will be requested and re‐analysed using multilevel models which control for clustering. Following this, effect sizes and standard errors will be meta‐analysed in RevMan using the generic inverse method (Higgins 2008). If appropriate controls were not used and individual participant data is not available, statistical guidance will be sought from the Cochrane Method Group and external experts as to which method to apply to the published results in attempt to control for clustering. If there is insufficient information to control for clustering, outcome data will be entered into RevMan using individuals as the units of analysis, and then sensitivity analysis will be used to assess the potential biasing effects of inadequately controlled clustered trials (Donner 2001).
(b) Crossover trials
When conducting a meta‐analysis combining the results of crossover trials, we will use the inverse variance methods recommended by Elbourne (Elbourne 2002). Where data presented from a crossover trial is restricted (and more information is not available from the original investigators) we will use the presented data within the first phase only, up to the point of crossover.
(c) Multi‐arm trials
All eligible outcome measures for all trial arms will be included in this review.
Dealing with missing data
We will contact the original investigators to request any missing data and information on whether or not it can be assumed to be ‘missing at random’.
For dichotomous data: we will report missing data and dropouts for each included study and will report the number of participants who are included in the final analysis as a proportion of all participants in each study. We will provide reasons for missing data in the narrative summary and will assess the extent to which the results of the review could be altered by the missing data by, for example, a sensitivity analysis based on consideration of 'best‐case' and 'worst‐case' scenarios (Gamble 2005). Here, the 'best‐case' scenario is that where all participants with missing outcomes in the experimental condition had good outcomes, and all those with missing outcomes in the control condition had poor outcomes, and the 'worst‐case' scenario is the converse (Higgins 2008, section 16.2.2).
For missing continuous data, we will provide a qualitative summary. The standard deviations of the outcome measures should be reported for each group in each trial. If these are not given, we will impute standard deviations using relevant data (for example, standard deviations or correlation coefficients) from other, similar studies (Follmann 1992) but only if, after seeking statistical advice, to do so is deemed practical and appropriate.
We will report separately all data from studies where more than 50% of participants in any group were lost to follow‐up, and will exclude these from any meta‐analyses. In studies with less than 50% drop out rate, we will consider people leaving early to have had the negative outcome, except for adverse effects such as death. The impact of including studies with high attrition rates (25 to 50%) will be subjected to sensitivity analysis. If inclusion of data from this group results in a substantive change in the estimate of effect of the primary outcomes, we will not add data from these studies to trials with less attrition, but will present them separately.
Assessment of heterogeneity
We will assess the extent of between‐trial differences and the consistency of results of any meta‐analysis in three ways: by visual inspection of the forest plots, by performing the Chi squared test of heterogeneity (where a significance level less than 0.10 will be interpreted as evidence of heterogeneity), and by examining the I2 statistic (Higgins 2008; section 9.5.2). The I2 statistic describes approximately the proportion of variation in point estimates due to heterogeneity rather than sampling error. We will consider I2 values less than 30% as indicating low heterogeneity, values in the range 31% to 69% as indicating moderate heterogeneity, and values greater than 70% as indicating high heterogeneity. We will attempt to identify any significant determinants of heterogeneity categorised at moderate or high.
Assessment of reporting biases
Funnel plots (effect size versus standard error) will be drawn to assess publication bias if sufficient studies are found. Asymmetry of the plots may indicate publication bias, although they may also represent a true relationship between trial size and effect size. If such a relationship is identified, the clinical diversity of the studies will be further examined as a possible explanation (Egger 1997).
Data synthesis
We will undertake a quantitative synthesis of the data using both fixed and random effects models. Meta‐analysis will be performed where we consider studies to have sufficiently similar participants, interventions, comparators and outcome measures. In carrying out meta‐analysis, the weight given to each study will be the inverse of the variance so that the more precise estimates (from larger studies with more events) are given more weight.
In addition, the weighted average of the results of all the available studies will be used to provide an estimate of the effect of antiepileptic drugs for aggression and impulsiveness. Where appropriate and if a sufficient number of studies are found, we will use regression techniques to investigate the effects of differences in the study characteristics on the estimate of the treatment effects. Statistical advice will be sought before attempting meta‐regression. If meta‐regression is performed, this will be executed using a random effects model.
Subgroup analysis and investigation of heterogeneity
If sufficient studies are found, we will undertake subgroup analysis to examine the effect on primary outcomes of:
(1) participants’ age
(2) participants’ principal diagnosis, e.g. personality disorder, learning disability, ADHD)
(3) setting (inpatient; custodial; outpatient/community)
(4) class of antiepileptic drug
Where we find a number of studies with participants aged less that 18 years, we will perform sensitivity analysis to explore the effect of including/excluding this younger sample.
Sensitivity analysis
If there is sufficient data, we will undertake sensitivity analyses to investigate the robustness of the overall findings in relation to certain study characteristics. A priori sensitivity analyses are planned for:
(1) concealment of allocation
(2) blinding of outcome assessors
(3) extent of dropouts
