Efficacy and Tolerability of Carbamazepine in Management of Aggression in Brain Injury, Dementia, and Neuropsychiatric Conditions: A Systematic Review of Clinical Trials

 

Tariq Khan

Rafey A. Faruqui

Abstract

Aim/ Objective

To evaluate efficacy and tolerability of Carbamazepine in management of aggressive behaviour in patients with acquired brain injury, dementia, and other neuropsychiatric conditions

Method

We searched electronic databases MEDLINE, PubMed, Psychinfo, TRIP, Embase and Google scholar.

Search terms: head injury OR brain injury OR acquired brain injury OR neurobehavioral disorders OR traumatic brain injury OR episodic dyscontrol OR aggression OR agitated behaviour OR dementia OR neuropsychiatric disorder AND carbamazepine.

Analysis:

Quality of studies was assessed using Jadad Quality Scoring Scale. Jadad scoring scale is a 5 point scale which is used routinely for assessing the quality of RCTs. A score of 0 is indicative of poor quality of study whereas, score of 5 is an indicator of an excellent study. We calculated Numbers Needed to Treat (NNT) and extracted relevant data on treatment efficacy and tolerability

Results:

Only RCTs in English language were included. The number of RCTs retrieved was 50, only 5 were relevant to the study question. 2 of these trails were relevant to dementia and 3 were relevant to brain injury. Tolerability data identifies certain safety concerns in connection with recommending this drug for wider use in neuropsychiatric population, especially elderly patients. The review does provide some evidence of efficacy of this medication that requires replication.

Key words:

Carbamazepine, aggression, brain injury, head injury, dementia, neuropsychiatric disorders

 

Introduction:

Since its introduction in 1953 as an anticonvulsant by chemist Walter Schindler, Carbamazepine has found diverse additional uses in clinical practice and more recently carbamazepine is being advocated for the control of aggressive behaviour [1].

The first reported use of Carbamazepine in Psychiatry dates back to 1971 when in Japan, Takezaki and Hanaoka used Carbamazepine to control mania in patients considered refractory to antipsychotics medication [2]. De Vogelaer in 1981 [3], and Hakola and Laulumaa in 1982 [4] reported using Carbamazepine in order to control aggressive behaviour. They reported that a mean dose of 600 mg/day of carbamazepine, added to high doses of neuroleptics, made a significant difference in all eight of their violent female patients.

Carbamazepine is an anticonvulsant and mood-stabilizing medication used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia. It is also used off-label for a variety of other indications, including attention-deficit hyperactivity disorder (ADHD), schizophrenia, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, and post-traumatic stress disorder.

In neuropsychiatric disorders such as brain injury, dementia, episodic dyscontrol, and Huntington’s disease, this medication is often used for control of aggression and behavioural disturbance.  Carbamazepine works by stabilizing the inactivated state of voltage-gated sodium channels, making fewer of these channels available to subsequently open. Thus, this leaves the affected cells less excitable until the drug dissociates.

The common adverse effects of this medication may include drowsiness, headache, motor coordination impairment, gastric symptoms due to stomach irritation and risk of developing lupus in women [5]. Less common side-effects may include cardiac arrhythmias, blurred vision, diplopia, agranulocytosis and auditory side effects [6-7]. Additionally, carbamazepine may possibly exacerbate pre-existing cases of hypothyroidism, so yearly thyroid function tests are advisable for persons taking Carbamazepine. Carbamazepine increases the rate of metabolism of numerous other medications [8-16].

Baseline studies before starting carbamazepine should include a FBC (Full Blood Count) with platelet count, liver and thyroid function tests, serum electrolytes, ECG (Electrocardiogram), and urinalysis. It is usual to begin with a dose of 200 mg/day and increase it slowly, while observing for therapeutic effect. At two to four weeks, the serum drug level may dip due to auto induction [9]. It is advisable that the FBC and platelet count should be checked regularly to monitor for risk of developing agranulocytosis. An idiosyncratic reaction requiring withdrawal of the drug is likely if the platelet count drops; a drop in the leukocyte count can be addressed more flexibly. Once the carbamazepine dose is stable, its plasma level along with FBC, platelet count, electrolytes, and liver function tests should be monitored every three to six months.

 

Aims / Objectives of study:

To evaluate efficacy and tolerability of Carbamazepine in management of aggression in brain injury, dementia, and neuropsychiatric conditions.

The main aims of this study were to obtain answer for two questions;

1)         What is the quality of evidence on efficacy of Carbamazepine in management of agitation and aggression in acquired brain injury, dementia, and neuropsychiatric conditions?

2)         What is the evidence of tolerability in different patient groups?

 

Method:

 Systematic literature reviews and meta-analyses have assumed an increasingly central role in healthcare literature during the past decade [17]. Systematic reviews of all relevant

research about the efficacy of a treatment are increasingly seen by clinicians, healthcare providers and funding agencies as providing the most reliable basis evaluating treatment effectiveness [18].

A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question [19]. Researchers conducting systematic reviews use explicit methods aimed at minimizing bias, in order to produce more reliable findings that can be used to inform decision making.

Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine. A systematic review uses a process to identify comprehensively all studies for a specific focused question (drawn from research and other sources), appraise the methods of the studies, summarize the results, present key findings, identify reasons for different results across studies, and cite limitations of current knowledge  [20].

We searched electronic databases including MEDLINE, PubMed, Psychinfo, TRIP, Embase and Google scholar. Search terms: head injury OR brain injury OR acquired brain injury OR neurobehavioral disorders OR traumatic brain injury OR episodic dyscontrol OR aggression OR agitated behaviour OR dementia OR neuropsychiatric disorder AND carbamazepine.

Quality of studies was assessed using Jadad Quality Scoring Scale. Jadad scoring scale is a 5 point scale which is used routinely for assessing the quality of RCTs [21]. A score of 0 is indicative of poor quality of study whereas, score of 5 is an indicator of an excellent study. In order to increase the credibility and validity of the results Investigator triangulation method was used where quality was analysed by two ratters [22] and the third partner acted as an arbitrator where clarification required or disagreement needed resolving.

It was not possible to create a meta-analysis of the results due to the heterogeneity of data and a very few research studies selected for final analysis.

Table 1. Quality Analysis Using Jadad Scoring

Jadad Scoring Criteria

Azouvi et al, 1998 ( efficacy and tolerability )

Smith et al, 1994 ( describing tolerability or side effects)

Tarriot et al, 1995 ( describing tolerability or side effects)

Tarriot et al, 1998 ( efficacy and tolerability)

Tarriot et al, 1999 (describing tolerability or side effects)

Study described as Radomised (+1)

( this study is prospective open trial and not randomised )

 

+1

 

0

 

+1

( this study is a follow-up of trial reporting non randomised group)

Randomisation method described and appropriate to conceal allocation (+1) 

 

  0

 

+1

 

0

 

+1

 

  0

Randomisation method described but inappropriate (-1) 

 

  0

 

0

 

0

 

-1

 

 0

The study described in double blinded ( +1)

 

  0

 

+1

 

+1

 

+1

 

  0

The double blinding described appropriate to maintain blinding ( +1)

 

  0

 

+1

 

0

 

+1

 

  0

Blinding method is inappropriate ( -1)

 

  0

 

0

 

-1

 

0

 

  0

Withdrawal and drop outs described ( +1)

 

  0

 

+1

 

+1

 

+1

 

  0

Final score ( max 5)

 

  0

 

5

 

1

 

4

 

  0

 

Results:

Only randomised controlled trials (RCTs) in English language were included. The number of RCTs retrieved during initial search was 50. Of these we excluded 45 because they did not meet our inclusion criteria and only 5 studies were relevant to the study question.

In medical pharmacology literature, efficacy (Emax ) refers to the maximum  response achievable from a drug [23] which produces a desired beneficial change of a given intervention (e.g. a drug).  Tolerability refers to how tolerable in terms of side effects a medication is. Both, efficacy and tolerability are crucial parts of any study which provide important information on effectiveness and safety of a given intervention.

Article summaries are divided into efficacy and tolerability subsections.

 

A: Efficacy

  1. [24] Azouvi et al, 1998, Closed-Head Injury, Prospective Open Trial-8 Week Duration:

10 subjects with agitation and anger outbursts, dose range 400- 800 mg per/day. Results: Improvement in irritability, disinhibition, agitated behaviour, and social functioning without adverse impact on global cognitive functioning.

  1. [25] Tariot et al, 1998, Randomized, Multi-site Parallel Group Study on Agitation and Aggression in Dementia. Trial Duration 6 Weeks: 51 subjects with agitation and dementia on carbamazepine were compared with placebo. Carbamazepine dose at 6 weeks was 300 mg/day, and a mean serum level of 5.3 micrograms/ml. Results showed significant short-term efficacy of carbamazepine for agitation with generally good safety and tolerability.

It was not possible to generate an evidence based mathematical summary for study 1 due to lack of a control group. We calculated odds ratio (13.3) and Number Needed to Treat (2) for Study 2 as reported in Table 2

Table 2: Efficacy of Carbamazepine Based on NNT calculated From a Single Study

 

 

Outcome Positive

 

Outcome Negative

 

Total

Experiment/ Intervention Group

 

 

 21

 

6

 

27

 

Control

 

 

5

 

19

 

24

 

Total

 

26

 

25

 

 51

 

B: Tolerability:

  1. [26] Smith et al, 1994, Double-Blind, Placebo-Controlled Study of Seizure Prophylaxis after Brain Injury, Trial Duration 6-44 Months: Reporting tolerability in terms of cognitive and emotional performance and comparing carbamazepine (42) with Phenytoin (40). No significant differences were found in the performance of patients in medication and placebo groups for either drug.
  1. [27] Tariot et al, 1999, Follow-up Continuation of trial reported as number 2 above; 6-12 Week Follow-up: Withdrawal from controlled carbamazepine therapy followed by further carbamazepine treatment in patients with dementia: group treated with modal Carbamazepine dose of 300 mg/day. Results concluded an improvement in measures of agitation and aggression. 2 deaths and 4 adverse events resulted in attrition from the group. Neither of the deaths was attributed to Carbamazepine: only one serious adverse event was linked to this medication.
  1. [28] Tariot et al, 1995, Non-Randomized, Double Blind, Placebo-Controlled Crossover Study, 25 Subjects with Dementia: Carbamazepine and placebo during two 5-week periods separated by a 2-week washout. The modal dose was 300 mg/day. Results indicated that carbamazepine in this dose range was well tolerated for the 5-week treatment period in this frail elderly sample.

A close evaluation of above studies identified additional safety and side effects concerns. Tolerability data is summarized in table 3

Table 3. Tolerability, Study characteristics and outcome measures

Author/ Study

Number of paricipants (Cases, controls)

Age (Mean)

Reported adverse effects/ Attrition attributed to side effects  (numbers)

Outcome measure used

Azouvi et al, 1998

Carbamazepine in agitation and aggression following closed-Head Injury,

(dose range 400-800 mg./ day)

10 (no control group)

33.7 Years

1 case of allergic reaction and  4 cases of drowsiness

NRS-R ( Neurobehavioural Rating Scale Revised), KAS ( Katz Adjustment Scale), MMSE ( Mini mental State Examination)

Smith et al, 1994, Study of Seizure Prophylaxis after Brain Injury. Cognitive side effects profile was assessed using neurocognitive measures during treatment and following withdrawal of treatment

(carbamazepine dose range: Not given)

82 (40-Phenytoin Group, 42 carbamazepine Group)

Age Range 16-65 (Mean not reported)

withdrawal of medication resulted in improvement of cognitive performance, seen particularly on tasks  requiring significant motor and speed performance.

– improvement in the speed of reading performance,

– trend towards improvement of delayed recall of verbal memory.

Stroop, Trail making, Digit Symbol, Randit Memory test, Paired Words, Benton Visual retention, Verbal Fluency Test, Beck Depression Scale, State Trait Anxiety Scale

Tariot et al, 1998 Study on Agitation and Aggression in Dementia.

 

(modal dose: 300 mg/day)

51 (Carbamazepine-27, Placebo-24)

86 Years

2 cases of clinically significant adverse effects on Carbamazepine; 1 case of tics and 1 case of severe ataxia. 12 cases of falls, 7 GI distresses, 8 drowsiness, 9 ataxia, 8 light headedness, 5 postural instability and 4 cases of disorientation.

BPRS ( Brief Psychiatric rating Scale), CGI ( Clinical Global Impression)

Tariot et al, 1999 Withdrawal from  carbamazepine therapy followed by further carbamazepine treatment in patients with dementia

 

(modal dose: 300 mg/day)

47 (control conditions and group separation were removed-open label). Only 25 subjects remaining in trial at week 21 end point.

86 Years

1 case of serious adverse effect (ataxia) attributable to Carbamazepine therapy. Authors further reported 11 incidents of fall with injury and 6 without injury; incidents of postural instability 10, fatigue/drowsiness 7, light headedness 4, fainting 2 and disorientation 2 . There were 2 deaths; neither of deaths attributed to carbamazepine. 

13 incidents of Gastrointestinal symptoms, 8 incidents of cardiorespiratory problems and 4 cases of musculoskeletal pain during trial period.

BPRS ( Brief Psychiatric rating Scale), MMSE ( Mini mental State Examination), CGI ( Clinical Global Impression), PSMS ( Physical Maintenance Scale), BRSD (Behaviour Rating Scale for Dementia), Laboratory blood tests

Tariot et al, 1995 To assess the effects of carbamazepine and placebo on measures of toxicity in frail nursing home patients

 

(modal dose: 300 mg/day)

25 (placebo-controlled crossover design)

84.5 Years

Carbamazepine related 34 separate adverse events were recorded among 22 patients; mostly seen were 19 cases of drowsiness and 50 involuntary movements with 1 case of fever. There was 1 reported death secondary to pneumonia.  Total drop outs= 2

NIMH Physical Signs & Symptoms Scale, Laboratory blood tests,, MMSE ( Mini mental State Examination),Physical Self Maintenance Scale

 

Discussion:

Carbamazepine is an anticonvulsant and mood-stabilizing medication used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia. It is also used off-label for a variety of other indications, including attention-deficit hyperactivity disorder (ADHD), schizophrenia, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, Myotonia congenita and post-traumatic stress disorder. In Neuropsychiatry Carbamazepine is often used for aggression in Brain Injury [29], Dementia [30], Episodic Dyscontrol and management of aggression and mood dysregulation associated with  Huntington’s disease [7].

Structural damage to brain, brain lesions and neurodegenerative conditions are known to be associated with aggressive behaviour. These behavioural manifestations present significant challenge in patient management and are known to be associated with treatment default, patient injury, staff burn out, disruption of care environment both in hospital based treatment setting and in residential and nursing care facilities.

Aggressive behaviour and agitation not only reduces the opportunity for patients to engage in rehabilitation but also becomes a major stressor for patients and their caregivers. Furthermore, a prolonged agitation period may reduce functional independence, induce a longer hospital stay, delay or prevent a return to work, and disturb family dynamics and community integration[31-35] which further complicates the rehabilitation of patients after acquired brain injury and sometimes such challenging patients are excluded from rehabilitation due to their constant challenging behaviour [36].

Numbers of pharmacological agents have proven to be efficacious in management of aggression and agitation presenting with psychiatric disorders. These medications include use of lithium for example for management of aggressive behaviour associated with different conditions and also using antiepileptic mood stabilizers in management of behavioural presentation associated with mood disorders and psychotic illnesses. Other commonly used medications in management of aggression and agitation after acquired brain injury include antidepressants, antipsychotics, beta-blockers, and neurostimulants. Although pharmacological intervention can be beneficial, detrimental side effects at times may be more harmful than the untreated agitation and aggression. In addition, medication-induced drowsiness can interrupt patient participation in their therapies [37-38].

Pharmacological agents are widely used in neuropsychiatric presentations especially for management of behavioural presentations. However, the overall, evidence based regarding pharmacotherapy use in management of behavioural presentations associated with the brain disorders remains limited.

A Cochrane review by Simon Fleminger evaluated the effects of drugs for agitation and aggression following acquired brain injury [39]. Fleminger concluded that numerous drugs have been tried in the pharmacological management of aggression after acquired brain injury but lack firm evidence of their efficacy. According to Fleminger Beta-blockers have the best evidence for efficacy [39].

Pharmacological agents are widely used for other types of neuropsychiatric conditions such as dementia. It is now known that use of certain groups of medication such as antipsychotic medication may be associated with risk of vascular side effects and stroke and some anti-dementia medication may not be very well tolerated. Antiepileptic mood stabilizers are frequently used but without robust evidence based on efficacy tolerability of this medication group in this patient population.

The aim of our study was to evaluate the efficacy and tolerability of Carbamazepine in management of aggression in brain injury, dementia and neuropsychiatric conditions. The study used a robust data collection that has been reported in the above sections of this report. Despite a robust search strategy only a small number of studies were identified as it appears the overall evidence of efficacy of this medication remains rather limited in neuropsychiatric settings.

Study by Tarriot et al [25] provides good evidence of efficacy of this medication in dementia group with NNT-2 and an odds ratio- 13.3. This was a short duration study and despite clarifying efficacy issues in the short term, it did not clarify tolerability issues sufficiently.

Our systematic review revealed that interpretation of tolerability data requires caution.  Apart from adverse effects (drowsiness, ataxia, falls) there were 2 reported deaths in one of the studies [27].  Carbamazepine may present with dose dependent side effects and a toxicity profile that is also not sufficiently and fully addressed in other studies as well. There are methodological and data collection issues such as not using structured side effects rating instruments to systematically study tolerability issues.

A significant finding in our study was NNT of 2 for a study population, it is important to know that this NNT has been established on the basis of a single study and we did not find another study that was able to replicate this result therefore, we advise caution in interpretation of these results.

It was not possible to calculate NNT for other trials’ data due to limitations of reporting in published trials. However, there have been important results in terms of tolerability suspected serious drug reactions and death during trial periods. We advise caution in general use of carbamazepine in management of agitation and aggression in dementia patients as there is a high possibility that this medication may be associated with significant side effect profile in the elderly patient group.

 

Conclusion:

There is some evidence that Carbamazepine works in the management of aggression in brain injury, dementia, and neuropsychiatric conditions, however, our analysis and the tolerability data identifies a number of safety concerns in connection with recommending this drug for wider use in neuropsychiatric population.

The review does provide limited evidence of efficacy of this medication.

Conflict of interests:

None

Funding acknowledgements:

None

 

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About the authors

Tariq Khan is a Consultant Psychiatrist at the HMP Norwich Mental Health Inreach and Rafey Faruqui is a Consultant Neuropsychiatrist at Kent and Medway NHS and Social Care Partnership Trust as well as a Professor at the University of Kent.