The CITIMERIVA Study: CITIcoline plus MEmantina plus RIVAstigmine in Older Patients Affected with Alzheimer’s Disease

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Combined therapy of memantine or acetylcholinesterase inhibitors, with cholinergic precursors such as citicoline, can be effective in Alzheimer’s disease. Indeed, they are able to increase the intrasynaptic levels of acetylcholine more than the single drug. Our aim was to evaluate the efficacy and safety of oral citicoline plus memantine plus rivastigmine in patients with Alzheimer’s disease.


This was a multi-centric, retrospective case-control study conducted in Italian Centers for Cognitive Impairment and Dementia on consecutive patients aged 65 years or older affected with Alzheimer’s disease. Overall, 104 patients were recruited (27% male, mean age 76.04 ± 4.92 years); 41 (39.42%) treated with citicolin 1000 mg/day given orally + memantine + rivastigmine (Cases) and 63 (60.58%) treated with memantine + rivastigmine (Controls). At baseline (T0), month 6 (T1) and month 12 (T2), cognitive functions were assessed by the Mini Mental State Examination (MMSE), functional dependence by basal Activities (ADL) and Instrumental Activities of Daily Living (IADL), comorbidity by the Cumulative Illness Rating Scale (CIRS), mood by the Geriatric Depression Scale (GDS), and behavioural disturbances by the Neuropsychiatric Inventory (NPI). Adverse events were reported during the study.


The difference in MMSE score was not significant when comparing the two groups at T0, T1 or T2. However, in the case group, the MMSE total score showed a statistically significant difference at T0 versus T1 (13.63 ± 2.46 vs. 14.17 ± 2.24; p = 0.008), and at T0 versus T2 (13.63 ± 2.46 vs. 14.32 ± 2.53; p = 0.002). In the control group, no statistical differences were found at baseline (T0), T1 and T2. ADL, IADL, GDS and NPI total score did not improve during the study in either the case or the control group.


In our study we observed absence of a statistically significant difference between case and control groups for the MMSE total scores. However, in the case group in the MMSE total scores, there was a statistically significant increase between the baseline and the end of the study.

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The authors thank Miss Elisa Manzo for revising the English language. The research was carried out in accordance with national requirements and conforms to the principles embodied in the 1964 Declaration of Helsinki ( as well as to the International Ethical Guidelines for Biomedical Research Involving Human Subjects and the International Guidelines for Ethical Review for Epidemiological Studies ( Patients signed informed consent forms for treatment of their personal data and medical records. The ethics committee approved the study protocol. The authors have no commercial affiliation or other arrangements that could be considered to pose a conflict of interest regarding the submitted article.

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Correspondence to Alberto Castagna.

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No funding was received for the conduct of this study.

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The ethics committee approved the study protocol.

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Author Contributions

Conceptualization, AC, CM and GR; data curation, AC, AF, RL, CR and GR; formal analysis, AC, CM, AF and GR; writing and original draft preparation, AC, CM and GR; writing, review and editing, AC, CM and GR; supervision AC, CM, AF and GR. The final manuscript was seen and approved by all authors.

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Castagna, A., Manzo, C., Fabbo, A. et al. The CITIMERIVA Study: CITIcoline plus MEmantina plus RIVAstigmine in Older Patients Affected with Alzheimer’s Disease. Clin Drug Investig 41, 177–182 (2021).

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