Hostname: page-component-797576ffbb-k7d4m Total loading time: 0 Render date: 2023-12-07T17:38:13.768Z Has data issue: false Feature Flags: { "corePageComponentGetUserInfoFromSharedSession": true, "coreDisableEcommerce": false, "useRatesEcommerce": true } hasContentIssue false

Efficacy and safety of idalopirdine for Alzheimer’s disease: a systematic review and meta-analysis

Published online by Cambridge University Press:  18 December 2018

Shinji Matsunaga*
Department of Geriatrics and Cognitive Disorders, Fujita Health University School of Medicine, Toyoake, Japan
Hiroshige Fujishiro
Department of Psychiatry, Kawasaki Memorial Hospital, Kawasaki, Japan
Hajime Takechi
Department of Geriatrics and Cognitive Disorders, Fujita Health University School of Medicine, Toyoake, Japan
Correspondence should be addressed to: Shinji Matsunaga, Department of Geriatrics and Cognitive Disorders, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, 470-1192 Toyoake, Aichi, Japan. Phone: +81-562-93-9083; Fax: +81-562-93-9021. Email:



The efficacy and tolerability of idalopirdine, a selective 5-hydroxytryptamine6 receptor antagonist, in patients with Alzheimer’s disease (AD) is uncertain. A systematic review and meta-analysis of randomized controlled trials (RCTs) testing idalopirdine for patients with AD was performed.


We included RCTs of idalopirdine for patients with AD and used Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores as a primary measure.


Four RCTs with 2,803 patients with AD were included. There was no significant difference in ADAS-cog between the idalopirdine and placebo groups [mean difference (MD) = −0.41, P = 0.32, I2 = 62%]. However, significant heterogeneity remained. Sensitivity analysis revealed that idalopirdine was more effective than placebo for ADAS-cog in the high dose and moderate AD subgroups (high dose subgroup: MD = −2.15, P = 0.005, moderate AD subgroup: MD = −2.15, P = 0.005). Moreover, meta-regression analysis showed that idalopirdine effect size for ADAS-cog was associated with mean dose (coefficient, −0.0289), ADAS-cog at baseline (coefficient, −0.9519), and proportion of male participants (coefficient, 0.2214). For safety outcomes, idalopirdine was associated with a higher incidence of at least one adverse event and increased γ-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase, and vomiting than placebo. There were no significant differences in other secondary outcomes between both treatments.


Idalopirdine is not effective for AD patients and is associated with a risk of elevated liver enzymes and vomiting. Although idalopirdine might be more effective at high doses and in moderate AD subgroups, the effect size is small and may be limited.

Original Research Article
© International Psychogeriatric Association 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Atri, A. et al. (2018). Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA, 319, 130142. doi: 10.1001/jama.2017.CrossRefGoogle ScholarPubMed
Cummings, J. L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D. A. and Gornbein, J. (1994). The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology, 44, 23082314. doi: 10.1212/WNL.44.12.CrossRefGoogle ScholarPubMed
Dyer, S. M., Harrison, S. L., Laver, K., Whitehead, C. and Crotty, M. (2018). An overview of systematic reviews of pharmacological and non-pharmacological interventions for the treatment of behavioral and psychological symptoms of dementia. International Psychogeriatrics, 30, 295309.CrossRefGoogle ScholarPubMed
Erkkinen, M. G., Kim, M. O. and Geschwind, M. D. (2018). Clinical neurology and epidemiology of the major neurodegenerative diseases. Cold Spring Harbor Perspectives in Biology, 2, 10. doi: 10.1101/cshperspect.a033118.Google Scholar
Ferrero, H., Solas, M., Francis, P. T. and Ramirez, M. J. (2017). Serotonin 5-HT6 receptor antagonists in Alzheimer’s disease: therapeutic rationale and current development status. CNS Drugs, 31, 1932. doi: 10.1007/s40263-016-0399-3.CrossRefGoogle ScholarPubMed
Folstein, M. F., Folstein, S. E. and McHugh, P. R. (1975). “Mini-Mental State.” A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189198. doi: 10.1016/0022-3956(75)90026-6.CrossRefGoogle ScholarPubMed
Galasko, D. et al. (1997). An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. Alzheimer Disease and Associated Disorders, 11, S3339. doi: 10.1097/00002093-199700112-00005.CrossRefGoogle ScholarPubMed
Higgins, J. P., Thompson, S. G., Deeks, J. J. and Altman, D. G. (2003). Measuring inconsistency in meta-analyses. BMJ, 327, 557560. doi: 10.1136/bmj.327.7414.557.CrossRefGoogle ScholarPubMed
Hurst, N. P., Kind, P., Ruta, D., Hunter, M. and Stubbings, A. (1997). Measuring health-related quality of life in rheumatoid arthritis: validity, responsiveness and reliability of EuroQol (EQ-5D). British Journal of Rheumatology, 36, 551559. doi: 10.1093/rheumatology/36.5.551.CrossRefGoogle Scholar
Khoury, R., Grysman, N., Gold, J., Patel, K. and Grossberg, G. T. (2018). The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update. Expert Opinion on Investigational Drugs, 27, 523533. doi: 10.1080/13543784.2018.1483334.CrossRefGoogle ScholarPubMed
Lorke, D. E., Lu, G., Cho, E. and Yew, D. T. (2006). Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients. BMC Neuroscience, 7, 36. doi: 10.1186/1471-2202-7-36.CrossRefGoogle ScholarPubMed
Lundh, A., Lexchin, J., Mintzes, B., Schroll, J. B. and Bero, L. (2017). Industry sponsorship and research outcome. Cochrane Database Systems Review, 2, MR000033.Google ScholarPubMed
Maher-Edwards, G. et al. (2010). Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer’s disease. Current Alzheimer Research, 7, 374385. doi: 10.2174/156720510791383831.CrossRefGoogle ScholarPubMed
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G. and Group, P. (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ, 339, b2535. doi: 10.1136/bmj.b2535.CrossRefGoogle ScholarPubMed
Ramirez, M. J. (2013). 5-HT6 receptors and Alzheimer’s disease. Alzheimers Research & Therapy, 5, 15.Google ScholarPubMed
Rosen, W. G., Mohs, R. C. and Davis, K. L. (1984). A new rating scale for Alzheimer’s disease. The American Journal of Psychiatry, 141, 13561364. doi: 10.1176/ajp.141.11.1356.Google ScholarPubMed
Scheltens, P. et al. (2016). Alzheimer’s disease. Lancet, 388, 505517. doi: 10.1016/S0140-6736(15)01124-1.CrossRefGoogle ScholarPubMed
Schneider, L. S. et al. (2006). ADCS Prevention Instrument Project: ADCS-clinicians’ global impression of change scales (ADCS-CGIC), self-rated and study partner-rated versions. Alzheimer Disease & Associated Disorders, 20, S124138.CrossRefGoogle Scholar
Tricco, A. C. et al. (2018). Comparative effectiveness and safety of cognitive enhancers for treating Alzheimer’s disease: systematic review and network meta analysis. Journal of the American Geriatrics Society, 66, 170178. doi: 10.1111/jgs.15069.CrossRefGoogle Scholar
Wilkinson, D., Windfeld, K. and Colding-Jorgensen, E. (2014). Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer’s disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. The Lancet Neurology, 13, 10921099. doi: 10.1016/S1474-4422(14)70198-X.CrossRefGoogle ScholarPubMed
Winblad, B. et al. (2016). Defeating Alzheimer’s disease and other dementias: a priority for European science and society. The Lancet Neurology, 15, 455532. doi: 10.1016/S1474-4422(16)00062-4.CrossRefGoogle ScholarPubMed
Supplementary material: File

Matsunaga et al. supplementary material

Appendices S1-S5

Download Matsunaga et al. supplementary material(File)
File 640 KB