SSRIs for mild cognitive impairment to Alzheimer’s disease

Could selective serotonin reuptake inhibitors (SSRIs) help reduce the burden of Alzheimer’s disease and prevent decline from mild cognitive impairment?

An estimated 10% of people over 65 years of age, and 30% of people over 85 years of age, have dementia. Dementia is the second leading cause of death in Australia, and is the single greatest cause of disability in Australians older than 65 years of age. These numbers are expected to only increase with the ageing population. While there are many different forms of dementia, Alzheimer’s disease is the most common – accounting for 70% of people with dementia.

Alzheimer’s disease is a neurodegenerative condition and does not have a cure. It is characterised by ‘β-amyloid plaques’ found outside of brain cells, thought to impair brain synapses, and ‘tangles’ inside brain cells, thought to impair metabolic processes – causing cholinergic neuron destruction and low levels of acetylcholine.

Anticholinesterases such as donepezil, galantamine or rivastigmine reduce the apparent cholinergic deficiency by reducing the breakdown of acetylcholine. As Alzheimer’s disease is also thought to be associated with glutamate excess, an N-methyl-D-aspartate (NMDA) antagonist – memantine – which may reduce glutamate-induced neuronal degeneration may be used.

However, existing pharmacological management is limited in its effectiveness in reducing symptoms and improving quality of life, and does not slow the progression of the condition. The recent spate of failed clinical trials with new medicines intended to target these plaques and tangles has led to questions around the fundamental understanding of the pathophysiology behind Alzheimer’s disease. Therefore, the race is still on to find an effective pharmacological option.

The impact of SSRIs

Animal studies have found SSRIs improve cognition by reducing the levels of β-amyloid plaques found with Alzheimer’s disease. A recent in vitro study looking at binding interactions identified fluoxetine and paroxetine to be the most effective of the SSRIs at inhibiting Aβ β 42 aggregation – the major component of the s-amyloid plaques. However, detail around how this interaction occurs is not well understood.

In humans, several randomised and placebo-controlled trials (the majority ranging from 8–24 weeks in duration) have returned mixed results with regards to the effect of SSRIs on cognition in Alzheimer’s disease. SSRIs may also confer the additional benefit of preventing cognitive decline as depression in late life is also associated with an increased risk of Alzheimer’s disease.

In lieu of large-scale long-term prospective studies, researchers evaluated data sets from the longitudinal Alzheimer’s Disease Neuroimaging Initiative, to investigate the impact of SSRIs on prevalence, and risk of deteriorating from mild cognitive impairment to Alzheimer’s disease, and cerebral spinal fluid biomarkers.

A look at the data

A total of 755 data sets of participants without current depression were analysed. Patients were categorised according to whether they had a history of depression based on their medical history, and grouped at baseline as ‘cognitively normal control subjects’, ‘patients with mild cognitive impairment’ and ‘patients with Alzheimer’s dementia’.

The mean follow-up period was 691 days and the mean duration of antidepressant treatment was 2,256 days (SD=2,474, range=4–16,051), with 22.8% being treated for up to 1 year before baseline, 52.1% between 1 and 4 years, and 25.1% for more than 4 years.

While a history of depression was found to be associated with a higher risk of a baseline diagnosis of mild cognitive impairment, and an even higher risk of a baseline diagnosis of Alzheimer’s disease, it was not associated with an increased rate of conversion from mild cognitive decline to Alzheimer’s dementia.

When analysis (Kaplan-Meier survival analysis) was limited to the fi rst three years of the observation period, patients with mild cognitive impairment and a history of depression with long-term SSRI treatment had significantly lower probability of conversion to Alzheimer’s dementia compared with all other comparison groups. Benefits conferred by use of the SSRIs appeared to be lost after three years, and the probability of subsequent Alzheimer’s dementia became similar to that of all other groups. No differences were noted with the biomarkers.

Conclusion

Much more research is required to better understand how SSRIs affect Alzheimer’s disease, and how it might prevent decline from mild cognitive impairment. Prospective interventional studies are needed to better understand whether this is a class effect, as well as indicative doses and implications for clinical practice.

Certainly, studies delving further into the different patient subtypes such as early and late-life depression, type of antidepressant used and so on are required. More work is definitely warranted in this area if such a readily affordable and well tolerated medicine can help reduce the burden of Alzheimer’s disease for such a significant amount of time.

References

1. Tin G, Mohamed T, Shakeri A, Pham AT, Rao PPN. Interactions of Selective Serotonin Reuptake Inhibitors with β-Amyloid. ACS Chem Neurosci. 2019;10(1):226–34. At: https://www.ncbi.nlm.nih.gov/pubmed/30157623
2. Bartels C, Wagner M, Wolfsgruber S, Ehrenreich H, Schneider A, Alzheimer’s Disease Neuroimaging Initiative. Impact of SSRI Therapy on Risk of Conversion From Mild Cognitive Impairment to Alzheimer’s Dementia in Individuals With Previous Depression. Am J Psychiatry. 2018;175(3):232–41. At: https://www.ncbi.nlm.nih.gov/pubmed/29179578