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Efficacy of mood stabilisers in the treatment of impulsive or repetitive aggression: systematic review and meta-analysis

  • Roland M. Jones (a1), James Arlidge (a2), Rebecca Gillham (a2), Shuja Reagu (a2), Marianne van den Bree (a2) and Pamela J. Taylor (a2)...
Abstract
Background

Individuals with repetitive or impulsive aggression in the absence of other disorders may be diagnosed with intermittent explosive disorder according to DSM–IV, but no such diagnostic category exists in ICD–10. Mood stabilisers are often used off-license for the treatment of aggression associated with a variety of psychiatric conditions, but their efficacy in these and in idiopathic aggression is not known.

Aims

To summarise and evaluate the evidence for the efficacy of mood stabilisers (anticonvulsants/lithium) in the treatment of impulsive or repetitive aggression in adults.

Method

A meta-analysis of randomised controlled trials that compared a mood stabiliser with placebo in adults without intellectual disability, organic brain disorder or psychotic illness, identified as exhibiting repetitive or impulsive aggression.

Results

Ten eligible trials (489 participants) were identified A pooled analysis showed an overall significant reduction in the frequency/severity of aggressive behaviour (standardised mean difference (SMD) =–1.02, 95% CI −1.54 to −0.50), although heterogeneity was high (I 2 = 84.7%). When analysed by drug type, significant effects were found in the pooled analysis of three phenytoin trials (SMD =–1.34, 95% CI −2.16 to −0.52), one lithium trial (SMD =–0.81, 95% CI −1.35 to −0.28), and two oxcarbazepine/carbamazepine trials (SMD =–1.20, 95% CI −1.83 to −0.56). However, when the results of only those studies that had a low risk of bias were pooled (347 participants), there was no significant reduction in aggression (SMD =–0.28, 95% CI −0.73 to 0.17, I 2 = 71.4%).

Conclusions

There is evidence that mood stabilisers as a group are significantly better than placebo in reducing aggressive behaviour, but not all mood stabilisers appear to share this effect. There is evidence of efficacy for carbamazepine/oxcarbazepine, phenytoin and lithium. Many studies, however, were at risk of bias and so further randomised controlled trials are recommended.

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Copyright
Corresponding author
Roland M. Jones, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN. Email: jonesrm6@cf.ac.uk
Footnotes
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R.M.J. is supported by a Joint MRC/Welsh Assembly Clinical Research Training Fellowship (GO800450).

Declaration of interest

R.M.J. has been paid for delivering educational presentations for Eli Lilly and Company.

Footnotes
References
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9 Mercer, D, Douglass, AB, Links, PS. Meta-analyses of mood stabilizers, antidepressants and antipsychotics in the treatment of borderline personality disorder: effectiveness for depression and anger symptoms. J Pers Disord 2009; 23: 156–74.
10 Nose, M, Cipriani, A, Biancosino, B, Grassi, L, Barbui, C. Efficacy of pharmacotherapy against core traits of borderline personality disorder: meta-analysis of randomized controlled trials. Int Clin Psychopharmacol 2006; 21: 345–53.
11 Huband, N, Ferriter, M, Nathan, R, Jones, H. Antiepileptics for aggression and associated impulsivity. Cochrane Database Syst Rev 2010; 2: CD003499.
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Efficacy of mood stabilisers in the treatment of impulsive or repetitive aggression: systematic review and meta-analysis

  • Roland M. Jones (a1), James Arlidge (a2), Rebecca Gillham (a2), Shuja Reagu (a2), Marianne van den Bree (a2) and Pamela J. Taylor (a2)...
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eLetters

Do we need to treat aggression?

Dr Salman A Mushtaq, Speciality Registrar General Adult Psychiatry
16 February 2011

‘Once upon a time, plenty of children were unruly, some adults were shy, and bald men wore hats. Now all of these descriptions might be attributed to diseases—entities with names, diagnostic criteria, and an increasing array of therapeutic options’ (1).

Aggression in the absence of any disorder could just be that, aggression or in other words bad or criminal behaviour. Why are we so keento medicalise bad behaviour or any other behaviour which is not within the‘defined’ or accepted norms?

I think it is good thing that ICD has not yet included a diagnosis like ‘Intermittent explosive disorder’.While we have come a long way from the time when modern medicine was accused of being a major threat to the health in the world (2), have we gone too far in the opposite direction?

The problem of medicalisation is that it doesn’t stop at that but it’s only the beginning of a chaos that becomes out of control. Once you make a diagnosis than you have to treat the disorder. Often such conditions are treated with medications that are not licensed for such treatment which in itself is bad practice in many cases. All treatments have their side effects and people are exposed to unnecessary side effects. False hope is given to people, their families and the society. A culture is promoted where people want medical solution to all their problems rather than taking responsibility for their actions. The cost of all this adds up to a huge amount.

Finally we have to do research to look at the efficacy of these treatments which include RCTs and meta-analysis at a great cost. Many times the result is little or no evidence for efficacy of these treatments. One simple reason could be that in order for a treatment to beeffective there needs to be a proper target illness.

Jones et al (3) conclude that the use of mood stabilisers resulted inan overall reduction in aggression. However the results keeping in view the large heterogeneity and publication bias would suggest that there is actually not enough evidence to support this statement.

In the end authors recommend further randomised controlled trials. I would like to ask that is there enough evidence to justify the cost of such trials which will also include the time and efforts of some highly qualified and expensive professionals?

What about Schizophrenia and depression which remains the leading causes of morbidity across the world with still relatively limited optionsof treatments available?

References:

1.McLellan F. Medicalisation: a medical nemesis. The Lancet, Volume 369, Issue 9562, Pages 627 - 628, 24 February 2007

2.Ivan Illich, Medical nemesis, 1977. Bantam.

3.Jones RM, Arlidge J, Gillham R, Reagu S, van den Bree M, Taylor PJ. Efficacy of mood stabilisers in the treatment of impulsive or repetitive aggression: systematic review and meta-analysis. The British Journal of Psychiatry 2011 198: 93-98.

DOI: None
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Conflict of interest: None Declared

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Is there an effect of mood stabilisers on aggression?

Jakov K Zlodre, Psychiatry core trainee
15 February 2011

Jones et al1 consider the effectiveness of mood stabilisers in the treatment of impulsive or repetitive aggression. The authors give a definition of aggression but do not give a definition of mood stabiliser. Studies considering the use of phenytoin are included although phenytoin is not licensed as a mood stabiliser. Phenytoin may have mood-stabilising properties2, but it may be more accurate to describe it as an anticonvulsant given current clinical practice.

Analysis of those studies considered to be at low risk of bias (Jadadscore >2 and using an intention-to-treat analysis) shows that there is no statistically significant reduction in aggression. It would be instructive, if data were provided, to complete the meta-analysis using requested original data to allow intention-to-treat analysis of those studies that had not originally conducted such an analysis.

Meta-analyses are often at risk of publication bias of RCTs3 and it would seem appropriate in this case to address this risk by publishing a funnel plot or similar instrument. Any future trials should be registered in advance.

The authors conclude that there was an overall reduction in aggression in people treated with a mood stabiliser. They qualify this statement by saying that many studies included were at risk of bias. Giventhe large heterogeneity, the risk of publication bias and no effect when only low bias studies were considered, a more appropriate conclusion mighttherefore be that there is currently not enough evidence to support an effect of mood-stabilisers on aggression. This was the finding of a recentCochrane review.4

1. Jones RM, Arlidge J, Gillham R, Reagu S, van den Bree M, Taylor PJ. Efficacy of mood stabilisers in the treatment of impulsive or repetitive aggression: systematic review and meta-analysis. The British Journal of Psychiatry 2011 198: 93-98.

2. Mishory A, Yaroslavsky Y, Bersudsky Y, and Belmaker RH. Phenytoin as an Antimanic Anticonvulsant: A Controlled Study. Am J Psychiatry 2000; 157: 463 - 465.

3. Stern JM, Simes RJ. Publication bias: evidence of delayed publication in a cohort study of clinical research projects. BMJ 1997; 315: 640–645.

4. Huband N, Ferriter M, Nathan R, Jones H. Antiepileptics for aggression and associated impulsivity. Cochrane Database of Systematic Reviews 2010, Issue 2. Art. No.: CD003499. DOI: 10.1002/14651858.CD003499.pub3.

Author name and address:Dr Jakov K Zlodre,Oxford Clinic,Oxford Health NHS Foundation Trust,Littlemore Hospital,Oxford, OX4 4XN

Tel: 07810 376023Fax: N/A

Declaration of interests: none.
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Conflict of interest: None Declared

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