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A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer's disease. Physostigmine Study Group
Thal LJ, Schwartz G, Sano M, Weiner M, Knopman D, Harrell L, Bodenheimer S, Rossor M et al.. Neurology, 1996-12-01
Topic: Amyloid, tau and blood-test diagnosis
Objective A multicenter trial to evaluate the efficacy of controlled-release physostigmine salicylate, a cholinesterase inhibitor, was conducted in 1,111 mild-to-moderate Alzheimer's disease (AD) subjects. Design During dose titration, subjects received 18, 24, or 30 mg of physostigmine or placebo daily. After a 2-week washout period, 366 subjects with putative improvement were randomized to receive either placebo or their best dose of physostigmine in a 6-week double-blind trial. Nonresponding patients (439) were randomized to receive in a separate double-blind trial either placebo or their highest tolerated dose of physostigmine. The primary efficacy measures included the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS) and a Clinical Global Impression of Change (CGIC). Secondary measures included the Mini-Mental State Examination and two activities-of-daily-living scales. Results At the end of the 6-week double-blind phase, physostigmine-treated patients scored 1.75 points higher than placebo-treated patients on the ADAS (p = 0.003) and 0.26 points higher on the CGIC (p = 0.012) in the intent-to-treat analysis. There was no significant improvement on the secondary outcome measures. Patients failing to respond to physostigmine during the dose titration phase failed to respond on any of the outcome measures during the double-blind period of re-exposure. Common adverse events included nausea, vomiting, diarrhea, and anorexia. There were no significant changes in liver function tests. Conclusion This study demonstrated statistically significant differences between physostigmine and placebo on both a performance-based cognitive functioning instrument and a clinician's global evaluation. The magnitude of the effect size was small and occurred only in the subset of patients who responded in the initial dose titration study period. Nevertheless, the results suggest that in a subset of patients, physostigmine can induce a degree of cognitive improvement over 6 weeks of treatment.
Key findings
- Results At the end of the 6-week double-blind phase, physostigmine-treated patients scored 1.75 points higher than placebo-treated patients on the ADAS (p = 0.003) and 0.26 points higher on the CGIC (p = 0.012) in the intent-to-treat analysis.
- There was no significant improvement on the secondary outcome measures.
- There were no significant changes in liver function tests.
- Conclusion This study demonstrated statistically significant differences between physostigmine and placebo on both a performance-based cognitive functioning instrument and a clinician's global evaluation.
- Nevertheless, the results suggest that in a subset of patients, physostigmine can induce a degree of cognitive improvement over 6 weeks of treatment.
Why it matters
In this trial, controlled-release physostigmine produced small improvements on two primary symptom measures in some patients with mild to moderate Alzheimer's disease, but no significant improvement on secondary measures. The drug was also linked to more patients dropping out and more side effects like nausea and vomiting.
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Study details
- Participants366
- Evidence strengthHigh
How this study scored 68/100
Published in a leading specialty journal, and it is a randomised controlled trial. Scored zero for effect reported because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 65 of the 96 points we could judge it on, which is 68 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Neurology) |
| Journal's citation record | 4 / 4 | Neurology: journal h-index 525 (OpenAlex, 2026-10-29) |
| Study design | 11 / 12 | A randomised controlled trial (from PubMed type “Randomized Controlled Trial”) |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 1996 — older than 20 years, still counted |
| Sample size | 2 / 4 | 366 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 2 / 2 | Randomised and blinded or placebo-controlled (as stated in the record) |
| Times cited | 4 / 7 | Cited 80 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.5 citations a year over 32 year(s) since 1996 |
| Impact for its field and year | 4 / 6 | Cited 9.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 7 other studies in this library |
| Still being cited | 1 / 4 | Cited 4 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 8960716) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 65 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 65 of the 96 points we could judge it on is 68 out of 100. |
| Total | 68 / 100 | — |
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Read the original
May need a subscription Unpaywall, Europe PMC and OpenAlex found no free copy of the full text (checked 10 Oct 2026), so the publisher may charge for it. The PubMed abstract is free.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Thal, L. J., Schwartz, G., Sano, M., Weiner, M., Knopman, D., Harrell, L., et al. (1996). A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer's disease. Physostigmine Study Group. Neurology. https://doi.org/10.1212/wnl.47.6.1389
Vancouver
Thal LJ, Schwartz G, Sano M, Weiner M, Knopman D, Harrell L, et al. A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer's disease. Physostigmine Study Group. Neurology. 1996. doi:10.1212/wnl.47.6.1389. PMID: 8960716.
BibTeX
@article{thal1996-8960716,
author = {Thal, L. J. and Schwartz, G. and Sano, M. and Weiner, M. and Knopman, D. and Harrell, L. and Bodenheimer, S. and Rossor, M. and others},
title = {{A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer's disease. Physostigmine Study Group}},
journal = {Neurology},
year = {1996},
doi = {10.1212/wnl.47.6.1389},
pmid = {8960716},
url = {https://doi.org/10.1212/wnl.47.6.1389}
}
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