Key points from the evidence

The content of this evidence summary was up-to-date in March 2015. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Four very small short‑term randomised placebo‑controlled trials (RCTs: total n=97) with many limitations give conflicting results about the efficacy of carbamazepine for managing aggression, agitation and behavioural disturbances in people with dementia. Larger, longer‑term RCTs are required to confirm its efficacy and safety for this indication.

Regulatory status: off‑label. The topic was prioritised because there is uncertainty about the balance of risks and benefits of carbamazepine in people with dementia.

Effectiveness

  • A 12‑week crossover RCT (4 weeks' treatment, n=19) and a 6‑week RCT (n=21) found no statistically significant differences between carbamazepine and placebo in global behavioural symptom scores.

  • In a 17‑week crossover RCT (8 weeks' treatment, n=6), carbamazepine statistically significantly reduced aggression scores compared with placebo (p<0.05).

  • Global behavioural symptom scores improved statistically significantly with carbamazepine compared with placebo in a 6‑week RCT (n=51: p=0.0003), as did other measures of behaviour and aggression.

  • The studies have many limitations and do not give any information on the long‑term safety and efficacy of carbamazepine in older people with dementia.

Safety

  • In the largest RCT (n=51), adverse effects were statistically significantly more common with carbamazepine compared with placebo (p=0.03). Statistical analyses were not performed in the other RCTs.

  • According to the summary of product characteristics (SPC) for Tegretol, hyponatraemia, leukopenia, thrombocytopenia, eosinophilia, central nervous system (CNS) adverse reactions gastrointestinal disturbances, fluid retention and allergic skin reactions occur commonly or very commonly with carbamazepine (in 1 in 100 people or more).

  • CNS adverse effects such as drowsiness, dizziness and ataxia may potentially lead to falls and fractures, particularly in frail, older people.

Patient factors

  • No information is available comparing carbamazepine with other active treatments for managing aggression, agitation and behavioural disturbances in people with dementia.

  • Adverse effects are particularly common in older people and carbamazepine has a high potential for drug interactions, which can increase toxicity. If CNS adverse effects are seen, the SPC suggests monitoring plasma levels and dividing the daily dosage into smaller fractional doses, both of which may be unacceptable to some patients.

Resource implications

  • The dosage of carbamazepine in the studies was usually 300−400 mg daily. The cost (excluding VAT) of 1 months' treatment with carbamazepine 400 mg daily ranges from £5.20 to £27.16 depending on the formulation (Drug Tariff, January 2015).

Introduction and current guidance

The NICE/SCIE guideline on dementia recommends non‑pharmacological interventions tailored to the individual person's preferences, skills and abilities as first‑line treatment. People who develop non‑cognitive symptoms or behaviour that challenges should be offered a pharmacological intervention in the first instance only if they are severely distressed or there is an immediate risk of harm to the person or others. Antipsychotic drugs have been associated with an increased risk of cerebrovascular adverse events and greater mortality when used in this population and NICE advises that treatment with an antipsychotic drug should be offered only after various conditions have been met. An acetylcholinesterase inhibitor or memantine may be offered in some circumstances.

Other drugs have been used off‑label for non‑cognitive symptoms of dementia; however, evidence to support their use is limited. The NICE full guideline on dementia concluded that there was insufficient evidence to support the use of anticonvulsant mood stabilisers, such as sodium valproate, valproate semisodium or carbamazepine, for the treatment of depression or anxiety in people with dementia. This evidence summary reviews the best available evidence for the use of carbamazepine for managing aggression, agitation and behavioural disturbances in dementia. It includes the 2 studies on carbamazepine that were considered by NICE (Olin et al. 2001 and Tariot et al. 1998) and 2 additional studies. Another evidence summary considers valproate preparations for these indications.

Full text of introduction and current guidance.

Product overview

Carbamazepine is licensed for treating epilepsy and trigeminal neuralgia, and preventing manic‑depressive psychosis in people who do not respond to lithium (see summaries of product characteristics for carbamazepine, for example, Tegretol tablets). It is not licensed for the management of aggression, agitation and behavioural disturbances in dementia; therefore, use for this indication is off‑label.

Full text of product overview.

Evidence review

  • This evidence summary is based on 4 very small randomised double‑blind placebo‑controlled trials (RCTs) that assessed the effects of carbamazepine in people with dementia and aggression, agitation or behavioural disturbances.

  • A crossover RCT by Chambers et al. (1982: not available online) included 19 inpatients with dementia and associated wandering, overactivity, restlessness or physical aggression. Participants received 4 weeks' treatment with carbamazepine or placebo, followed by a 3‑week washout period and 4 weeks' treatment with the alternative treatment. The study found no statistically significant differences between carbamazepine and placebo in global behaviour rating scores at any week over the 12‑week period.

  • A 17‑week crossover RCT by Cooney et al. (1996) included 6 people who had severe Alzheimer's disease and were verbally or physically aggressive. Participants received 8 weeks' treatment with carbamazepine or placebo, followed by a 1‑week washout period and 8 weeks' treatment with the alternative treatment. Treatment with carbamazepine reduced RAGE scale scores (a measure of aggression) statistically significantly more than placebo (p<0.05) but it is unclear whether the results were clinically important.

  • An RCT by Olin et al. (2001) included 21 people with severe Alzheimer's disease and significant agitation for over a month who had been treated unsuccessfully with antipsychotics. Only 16 people completed the 6‑week study. There was no statistically significant difference between the carbamazepine and placebo groups in Clinical Global Impression of Change or global Brief Psychiatric Rating Scale scores (BPRS: a measure of behaviour). The hostility item on the BPRS scale was statistically significantly improved with carbamazepine compared with placebo (difference 1.55 points on a 7‑point scale, p=0.009).

  • A 6‑week RCT by Tariot et al. (1998) included 51 people with severe Alzheimer's disease, vascular dementia or mixed dementia who had been significantly agitated for at least 2 weeks. Carbamazepine was statistically significantly more effective than placebo in improving global BPRS scores from baseline at week 6 (difference 6.8 points on a 126‑point scale; p=0.0003), mainly due to improvements in agitation and hostility (p=0.0001 and p=0.0007 respectively). Statistically significantly more people taking carbamazepine improved in terms of Clinical Global Impression compared with placebo (77% were at least minimally improved compared with 21% with placebo; p=0.001).

  • In Chambers et al. (1982), no participants discontinued treatment because of adverse effects but the authors reported that carbamazepine was 'poorly tolerated'. By contrast, carbamazepine was reported to be 'well‑tolerated' in the study by Cooney et al. (1996). In the study by Olin et al. (2001), 1 person in the carbamazepine group and 4 in the placebo group discontinued treatment (3 with agitation). Adverse events occurred in 4/9 people in the carbamazepine group and 8/12 people in the placebo group (p value not reported) and were reportedly 'mild'. Four people withdrew from the study by Tariot et al. (1998) (3 with severe agitation and 1 with tics and sedation), all of whom were taking carbamazepine. In this study, adverse effects were statistically significantly more common in the carbamazepine group than in the placebo group (16/27 people compared with 7/24 people; p=0.03), although these were considered clinically significant in only 2 people (1 with tics and 1 with ataxia).

  • According to the summary of product characteristics for Tegretol, central nervous system adverse reactions (dizziness, headache, ataxia, drowsiness, fatigue, diplopia), gastrointestinal disturbances (nausea, vomiting), fluid retention and allergic skin reactions occur commonly or very commonly with carbamazepine (in 1 in 100 people or more). This is particularly true when treatment is initiated, if the initial dosage is too high, and when treating older people. Other common or very common side effects include hyponatraemia, leukopenia, thrombocytopenia and eosinophilia.

  • The 4 RCTs have many limitations. For example, methods of randomisation and blinding were not reported in 3 studies and allocation concealment was not reported in any. All the studies were small and may have had insufficient power to detect differences between the treatment groups. Follow‑up was short so no information is available on the long‑term efficacy or safety of carbamazepine for managing aggression, agitation and behavioural disturbances in people with dementia. Also, all the studies were placebo‑controlled and it is not known how carbamazepine compares to other drugs that have been used for this indication. Although some outcomes measured using rating scales were found to be statistically significant in some studies, the effect sizes appear small and it is unclear whether they are clinically important.

  • The average age of people included in the 4 RCTs was 79 years and the majority (80%) were female, limiting applicability to men and younger people. The studies generally included people with severe dementia and it is unclear whether the results apply to people with less severe disease. Due to the potential for drug interactions and adverse effects, the dosage of carbamazepine should be selected with caution in older people.

Full text of evidence review.

Context and estimated impact for the NHS

The dosage of carbamazepine in the studies was usually 300−400 mg daily. According to the Drug Tariff (January 2015), the cost (excluding VAT) of 1 months' treatment with carbamazepine 400 mg daily ranges from £5.20 to £27.16 depending on the formulation (tablets, chewable tablets, modified release tablets or syrup).

Full text of context and estimated impact for the NHS.

Information for the public

A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non‑technical language and may be especially helpful for people with dementia who are thinking about trying carbamazepine.

About this evidence summary

'Evidence summaries: unlicensed or off‑label medicines' summarise the published evidence for selected unlicensed or off‑label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision‑making and support the construction and updating of local formularies.

The summaries support decision‑making on the use of an unlicensed or off‑label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.