Symptomatic drugs for cognitive impairment in dementia: what to expect?

Treatment of dementia is one of the greatest unmet needs in modern medicine. No pharmacological options for slowing or reversing the underlying process exist despite the tremendous effect on patients and a significant societal burden in terms of healthcare system costs and impact on the productivity, physical and mental health of family carers.

The only available treatments are symptomatic, with two separate classes of medication having been approved: cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and the NMDA antagonist memantine. The first class acts by slowing the breakdown of acetylcholinesterase, a neurochemical involved in attention and memory. The second counteracts the actions of one of the main neurochemicals in the brain, glutamate, which is thought to play a role in toxic overstimulation that is part of the disease process.

Clinical studies of these medications have shown a small but significant benefit to the cognitive ability (ie memory and thinking skills) of patients taking the drugs. On this basis, these drugs have been given licence in the UK to treat Alzheimer’s disease, with the National Institute for Health and Care Excellence (NICE) also recommending their use in dementia with Lewy bodies. Further studies have suggested that the drugs benefit the behavioural symptoms of dementia (agitation, hallucinations, low mood), which may explain why those who remain on the drugs despite worsening memory tend to avoid having to move into care facilities for longer.

Questions have been raised consistently about the risk-benefit of prescribing these medications. Most recently, France moved to defund their prescription, citing concern over minimal positive effects in the face of potentially significant side effects (for example, slowing of heart rate that may lead to falls and hospital treatment, and loose stool and other gut-related effects). While France remains the only European country to take this step, others – for example, Belgium – are considering this.

This trend requires an examination of the real-world effects of these medications that goes beyond what we know from controlled clinical studies. That is because such studies tend to set rigid criteria that govern who is allowed to take part, which invariably limits the degree to which their conclusions can apply to the clinical population in general. Because these studies provide a view of the effects of the medications in a highly controlled environment, their outcome is referred to as ‘effectiveness’, in contrast to the real-world ‘efficacy’.

The UK is ideally placed to investigate questions relating to the effectiveness-efficacy gap in psychiatry through the existence of UK-CRIS, a large dataset consisting of anonymised patient records from 12 mental health NHS trusts. In a study published in the British Journal of Psychiatry, we looked at data from over 7,400 individuals who had been prescribed symptomatic drugs for dementia. We searched the texts entered by clinicians to determine the effect that having been prescribed one these medications has on cognitive ability as measured by standard scales.

We found that symptomatic treatment led to a levelling off of the rate of cognitive decline for a period of two to five months. The effect was more pronounced in those with more severe forms of the disease. We also asked the question of whether changing to a different medication – a common practice in the clinic – associates with a benefit. A third of patients had to be changed to a different medication, and we could not find evidence that the change had an effect. In other words, our analysis suggests that up to a third of patients experience no benefit from these medications at all.

Our results represent the largest study to date, and can guide discussions between prescribers, patients and carers on the potential benefit of prescribing symptomatic treatment for dementia. It points to a sustained but short-lived benefit for most. For those who don’t respond to the first drug, the evidence does not support changing the drug.

What the study cannot address is what the effects of the drugs are on the behavioural symptoms of dementia (agitation, hallucinations, low mood and others), which tend to be the ones that place the greatest burden on carers and most frequently lead to patients moving into care facilities. Further work should also focus on the experience of being on these drugs from the point of view of the patients and carers.

While the currently available treatments are clearly imperfect, they do provide a degree of benefit which warrants a frank and informed discussion on the risk-benefit with the patient and their carers at the point of prescription.

Read the full study.