Last month I wrote a post on what we know about using medication for agitation and aggression. The post focused on a recently published paper by Dr Dallas Seitz and colleagues in 2013 (Seitz et al. 2013). Dr Seitz’s paper was a systematic review of all available evidence at the time looking at the efficacy of different drugs in the treatment of probably the most difficult symptoms to manage in dementia: neuropsychiatric symptoms in Alzheimer’s disease.

Just as my last blog was published, another more recent paper came to my attention. This time the paper is a systematic review and meta-analysis looking at exactly the same issue (Wang et al. 2014). The new paper includes more recent trials that had not been published by the time Dr Seitz and his colleagues completed their review. For that reason alone, I thought it would be worth covering in a new blog.

Methods

There are important differences in the two papers which are worth pointing out. The new paper by Dr Wang and colleagues is a meta-analysis and it only considers papers describing randomised controlled trials of a drug versus placebo. It also excludes any study not using the Neuropsychiatric Inventory (NPI) as its main outcome measure. The review focuses only on people with a diagnosis of probable or possible Alzheimer’s disease according to DSM-IV or National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association criteria. Other criteria they used to select studies included:

• Double-blind, placebo-controlled, randomised controlled trials (RCTs) with parallel or crossover design
• For crossover trials, washout period greater than 1 week
• Studies compared any medicine at any dose with placebo, with any treatment durations

They searched PubMed, EMBASE, the Cochrane Controlled Trials Register and the Cochrane Database of Systematic Reviews for reports published before December 2013. They searched using the condition, the names of drugs, and the symptoms and looked for hits in the title or abstract. They also looked at ‘bibliographies of reviews, original research articles and other articles of interest’. Their search was only done in English language published studies.

After searching and excluding they ended with a total of 32 studies that met criteria. Fifteen were on cholinesterase inhibitors, 8 on Memantine, 6 on atypical antipsychotics, 2 on antidepressants and 1 on mood stabilisers. The 32 trials included 6,812 participants on active treatment and 4,844 participants on placebo. Mean participant age ranged from 73.3 to 85.6 years. Mean baseline MMSE scores ranged from 4.5 to 21.2.

Results

As I did in my last post, I will summarise the results by type of agent.

Cholinesterase inhibitors

Studies included were 8 for donepezil, 4 for galantamine and 3 for metrifonate. Seven studies reported benefits for cholinesterase inhibitors. Two studies were excluded from the meta-analysis as they did not report on the mean change in NPI scores. Figure 1 below summarises the results.

Figure 1: Cholinesterase inhibitors vs placebo

It is worth mentioning that donepezil did not seem to differ significantly from placebo, whereas galantamine did. See figure 2.

Figure 2: Donepezil vs placebo and Galantamine vs placebo

The safety profile for cholinesterase inhibitors is summarised in figure 3 below.

Figure 3 – All cause dropouts (cholinesterase inhibitors)

Memantine

A total of 1,496 patients on memantine were compared with 1,333 patients on placebo. NPI measures were reported. There was no statistical difference between the groups. The results are in figure 4 below.

Figure 4: Memantine vs placebo

The results for all cause dropouts can be found on figure 5 below

Figure 5 – Memantine all cause dropouts

Atypical antipsychotics

Only 6 studies fully met inclusion criteria. One study (Sultzer et al, 2008) compared 3 drugs vs placebo and the results were extracted separately for each drug. There were a total of 1,561 participants on atypical antipsychotics compared with 950 participants on placebo. Figure 6 shows the results of the only positive comparisons which favoured aripiprazole and olanzapine.

Figure 6: Olanzapine vs placebo and Aripiprazole vs placebo

Figure 7: Summary of all-cause dropouts for atypical antipsychotics vs placebo

Antidepressants

There were only two trials that met inclusion criteria, both for sertraline. There was no effect.

Figure 8: Antidepressants vs placebo

Figure 9: Summary of all-cause dropouts for antidepressants vs placebo

 

Mood stabilisers

There was only one study that met inclusion criteria. The study compared sodium valproate used with 14 participants vs 13 participants on placebo. The result showed no significant differences between the groups. The size of the trial was so small that it is hard to draw any conclusions.

Conclusions

Taking this study and the one I reviewed last month together, the conclusions are still that there might be a slight advantage to using atypical antipsychotics in neuropsychiatric symptoms in Alzheimer’s disease. This study finds only aripiprazole and olanzapine are of use. There were no studies on Risperidone included. Another marked difference is the benefits from cholinesterase inhibitors that were observed by Wang et al, which were not evident at all in the Seitz review. Galantamine in particular seemed to be useful in this meta-analysis.

In terms of limitations, the authors only included English language papers and excluded studies that did not conform to a very specific study design with only one outcome measure. The review excluded studies looking at diagnoses other than Alzheimer’s disease and studies where only the diagnosis of dementia was required. I am surprised that there were no papers looking at benzodiazepines that met criteria for inclusion and the authors did not specifically list any on the list of terms used to search for papers. Studies comparing a drug versus a non-pharmachological intervention were excluded so we are no wiser as to how those perform.

All this aside, this study does provide a valuable synthesis of the evidence. The study is particularly useful in providing a look at those drugs for which multiple studies were found and for which we have data on large numbers of patients: cholinesterase inhibitors and atypical antipsychotics.

Impact on clinical practice

Based on this I believe my general plan as to how to approach the use of these agents in clinical practice still holds:

• Try to find any and all causes for the behaviour
• When using medication, use it with a clear measurable objective (use a scale) and for a time-limited trial
• If ineffective, stop
• If effective, withdraw it as soon as possible

However, based on this study, I will now be trying galantamine, as opposed to using antipsychotics only as my first line.

Links

Wang J, Yu JT, Wang HF, Meng XF, Wang C, Tan CC, Tan L (2014). Pharmacological treatment of neuropsychiatric symptoms in Alzheimer’s disease: a systematic review and meta-analysis. Journal of Neurology Neurosurgery and Psychiatry. doi:10.1136/jnnp-2014-308112. [Abstract]

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