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16 February 2018

Can acetylcholinesterase inhibitors and CNS stimulants tackle cognitive dysfunction in multiple sclerosis?

Cognitive dysfunction in multiple sclerosis (MS) presents a significant, unmet therapeutic need. Researchers at Cambridge Cognition and the University of Manchester investigated potential solutions to this problem with a systematic review and meta-analysis of pro-cognitive drug trials in MS. 

Multiple sclerosis (MS) can present differently in every patient, but this autoimmune attack on the central nervous system is thought to result in cognitive problems in up to 70% of patients, spanning all subtypes of the disease (Langdon, 2011; Prakash et al., 2008; Ruet et al., 2013). Despite the significant burden that can be posed by cognitive impairment on patients with MS and their carers, there are still no certified treatments. In an effort to identify potential solutions to this problem, a systematic review and meta-analysis of pro-cognitive drug trials in MS was conducted by researchers at Cambridge Cognition and the University of Manchester.

Reviewing pro-cognitive drug trials in MS

The paper: ‘Examining the effectiveness of acetylcholinesterase inhibitors and stimulant based medications for cognitive dysfunction in multiple sclerosis: A systematic review and meta-analysis’, published in Neuroscience and Biobehavioural Reviews, systematically compared the effectiveness of acetylcholinesterase inhibitors (AChEIs) and central nervous system (CNS) stimulant-based drugs for improving cognitive performance in MS, using data from 16 randomised, double-blind, placebo-controlled trials (Cotter et al., 2018).

Acetylcholinesterase inhibitors and stimulant based drugs offer no significant pro-cognitive effects over placebo in MS 

Acetylcholinesterase inhibitors (AChEIs) increase levels of acetylcholine in the brain; a neurotransmitter thought to promote learning and memory (Colovic et al., 2006). The AChEIs investigated for pro-cognitive effects in this systematic review and meta-analysis were donepezil and rivastigmine, which are both currently approved as symptomatic treatments for Alzheimer’s disease. The researchers reported that collectively, these drugs showed no significant beneficial effects over placebo in performance across a range of cognitive domains (Cotter et al., 2018).

CNS stimulant-based medications boost alertness (Ng & O’Brien, 2009), which may mitigate fatigue-driven cognitive dysfunction in MS. This systematic review and meta-analysis collectively investigated the efficacy of the following stimulants: methylphenidate, modafinil, L-amphetamine sulfate, and lisdexamfetamine dimesylate. Unfortunately, again no significant pro-cognitive effects were identified (Cotter et al., 2018).

Conclusions and future directions

In conclusion, both AChEIs and CNS stimulants failed to significantly improve performance on measures of processing speed, memory, or executive functioning in patients with MS. Further research still needs to be done to address this significant therapeutic need. It may be that there is no ‘single’ drug which can improve cognition in all patients with MS that are adversely affected due to differences in the underlying causes of these deficits. Given positive effects were reported in several of the original trials included in this review, post-hoc responder analyses of these existing studies may provide insights into specific subgroups of patients who were responsive to these drugs, providing impetus for research into more personalised pro-cognitive treatments in this population.

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Colovic, M. B., Krstic, D. Z., Lazarevic-Pasti, T. D., Bondzic, A. M., & Vasic, V. M. (2013). Acetylcholinesterase Inhibitors: Pharmacology and Toxicology. Current Neuropharmacology, 11(3), 315–335. https://doi.org/10.2174/1570159X11311030006

Cotter, J., Muhlert, N., Talwar, A., & Granger, K. (2018). Examining the effectiveness of acetylcholinesterase inhibitors and stimulant-based medications for cognitive dysfunction in multiple sclerosis: A systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews, 86(January), 99–107. https://doi.org/10.1016/j.neubiorev.2018.01.006

Hasselmo, M. E. (2006). The role of acetylcholine in learning and memory. Current Opinion in Neurobiology, 16(6), 710–715. https://doi.org/10.1016/J.CONB.2006.09.002

Langdon, D. W. (2011). Cognition in multiple sclerosis. Current Opinion in Neurology, 24(3), 244–249. https://doi.org/10.1097/wco.0b013e328346a43b

Ng, B., & O’Brien, A. (2009). Beyond ADHD and narcolepsy: psychostimulants in general psychiatry. Advances in Psychiatric Treatment, 15(4), 297–305. https://doi.org/10.1192/apt.bp.107.004879

Prakash, R., Snook, E., Lewis, J., Motl, R., & Kramer, A. (2008). Cognitive impairments in relapsing-remitting multiple sclerosis: a meta-analysis. Multiple Sclerosis Journal, 14(9), 1250–1261. https://doi.org/10.1177/1352458508095004

Ruet, A., Deloire, M., Charré-Morin, J., Hamel, D., & Brochet, B. (2013). Cognitive impairment differs between primary progressive and relapsing-remitting MS. Neurology, 80(16), 1501–8. https://doi.org/10.1212/WNL.0b013e31828cf82f

Tags : pro-cognitive | clinical trials | ms | multiple sclerosis | cognitive impairment | cognitive dysfunction

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Dr Jack Cotter