In the longest, most encompassing study yet, new results show that …

Galantamine’s Benefits
Require Continuous Use

A new, not yet published, large-scale international retrospective
study examines the use of galantamine for up to 7 years
By Will Block

If you want a long life, have a long list
[about the future; about stuff that you want,
people you want to see, things you want to do … ].

— Jack Wheeler,
the real Indiana Jones (as noted by
the Wall Street Journal)

E xpanding on the above quote: as important as a long list is to a long life, so is a long memory. Not to mention a short one … if you can’t find your list, what good is the it? Every thought … every emotion … every innovation … every memory … every “wow, that’s great!” is only possible because of what goes on in your precious mind. So it’s good to know that scientific research continues to demonstrate that certain nutrients can feed your mind and maintain your brain. Among these, as new findings once again show, is galantamine, a plant-derived acetylcholinesterase inhibitor (AChEI) that helps to preserve memory function by preventing a specific enzyme from prematurely breaking down the memory molecule acetylcholine (ACh), effectively increasing your brain levels of this neurotransmitter. But galantamine doesn’t stop there. In a nutshell, galantamine’s special advantages are:

  • Long-term efficacy—Galantamine works as well as or better than the drugs donepezil and rivastigmine as an AChEI, in part because, unlike those drugs, it does not induce drug tolerance. That means that the body does not become increasingly tolerant of it (which is to say, resistant to it), thereby causing it to become less and less effective. A major part of the reason for this virtue of galantamine has to do with its other principal virtue:

  • Modulation of nicotinic receptors—Galantamine does something the other AChEIs do not do: it modulates certain key receptors on our brain cells, called nicotinic receptors, in such a way as to preserve both their numbers and their functional integrity (this is important because nicotinic receptors are the primary receptors for acetylcholine). Absent this protective action, the nicotinic receptors in Alzheimer’s disease tend to deteriorate over time, and that contributes to drug tolerance with the other AChEIs. The symptoms of Alzheimer’s disease thus gradually become worse.

Taking Galantamine for 7 Years

A new, not yet published, large-scale international retrospective study, evaluated the long-term effects of galantamine on cognitive function in Alzheimer’s disease in terms of Mini-Mental State Examination (MMSE)* scores for up to 7 years, using both clinical data and epidemiological modeling.1 Summarizing its findings, the researchers wrote,

Results showed that patients with mild-to-moderate AD [Alzheimer’s disease] who received long-term galantamine treatment exhibited attenuated [lessened] decline in cognitive function, as assessed by MMSE, compared with decline predicted in the absence of treatment. Furthermore, patients who stopped treatment experienced subsequent cognitive decline at a rate similar to that predicted for untreated patients.


* The MMSE is a brief 30-point questionnaire test that is used to measure cognitive impairment, and in medicine to screen for dementia. It is also used to estimate the severity of cognitive impairment at a given point in time and to follow the course of cognitive changes in an individual over time, thus making it an effective way to document an individual’s response to treatment. In the time span of about 10 minutes it samples various functions including arithmetic, memory and orientation.


When the Long Term Counts

Alzheimer’s is the sixth-leading cause of death in the United States. According to conventional analysis, Alzheimer’s is the only cause of death in the top 10 that cannot be prevented, cured or even slowed.2 Strictly speaking, that is not true across the board. Nevertheless, based on mortality data from 2000–2008, death rates have declined for most major diseases, but not for Alzheimer’s, which has risen 66 percent during the same period. However, interpretation of the data may be confounded because of better reporting and the continued rise in the age of the population, in which Alzheimer’s disease is much more common.


“Results showed that patients with
mild-to-moderate AD [Alzheimer’s
disease] who received long-term
galantamine treatment exhibited
attenuated [lessened] decline in
cognitive function.”


Despite the predictable despair, median survival time after diagnosis may now be over 9 years, and this appears to be lengthening, especially for those who receive the finest care, and that includes taking the right supplements. Thus it is important to consider long-term effects, not only in those individuals receiving therapy, but also in subjects for whom therapy has been discontinued. According to the international retrospective study, by using clinical data and epidemiological modeling from a lengthy collection of studies, it is possible to analyze and place into perspective a far bigger picture than has been previously seen with regard to galantamine.

Building on Collected Conclusions

In placebo-controlled trials lasting as long as 6 months, galantamine has shown a variety of benefits in patients with mild and moderate Alzheimer’s: benefits for cognitive function, activities of daily living, behavior and global condition. When data from longer-term (3- to 4-years) open-label studies are considered, it can be concluded that galantamine may reduce the rate of cognitive decline, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog).* This is apparent when compared to an epidemiological prediction of untreated decline.


* In practice, however, the ADAS-Cog is rarely used. Alzheimer’s progression is more likely to be measured using the simpler MMSE.



“Furthermore, patients who stopped
treatment experienced subsequent
cognitive decline at a rate similar to
that predicted for untreated patients.”


While relatively few long-term studies (>1 year duration) using MMSE to evaluate Alzheimer’s patients receiving galantamine treatment have been published (mean follow-up, 3.8 years), the data shows that baseline MMSE scores are a significant predictor of nursing home admission. However, a long term randomized, placebo-controlled study using the AChEI drug donepezil found that the mean MMSE score after 2 years was 0.8 points higher (higher is better) for donepezil treatment versus placebo. Could this be true for galantamine too?


Patients withdrawn from treatment
experienced a subsequent
deterioration in cognition, even if
treated for at least one year.


Cognitive decline in patients with Alzheimer’s has been evaluated in previously published articles using different statistical methods. For example, one galantamine study showed that the annual deterioration in ADAS-Cog score was lower in subjects with mild or severe Alzheimer’s than in those with moderate Alzheimer’s. In a meta-analysis of 43 small studies of MMSE progression in patients with Alzheimer’s—where the median baseline score was 18.4, (at the borderline between mild and moderate), it was found that the average annual decline in MMSE score was 3.3 points. Indeed, as other studies have shown, the progression of Alzheimer’s is dependent on the stage of the disease.

While such models are able to predict MMSE decline in untreated patients, when treated with AChEIs such as galantamine, the results are not predictable, and must rely on the data obtained. Adding to analysis difficulty, MMSE decline is affected by patients who drop out of studies or who are lost to follow-up.

Comparing Those Who Continued and Those Who Did Not

What was unusual about the international retrospective was that it evaluated galantamine’s long-term effects on cognitive function in Alzheimer’s in terms of MMSE scores for up to 7 years of treatment. Also uncommon was that it considered cognitive effects not only in patients who continued to receive galantamine therapy, but, importantly, also in individuals who discontinued treatment.

Not only did the study explore the effects of galantamine therapy, it also did the same for treatment withdrawal. By using a retrospective epidemiological model to predict rates of cognitive decline in the absence of long-term placebo data, the new study has great relevance in the context of current treatment and research in Alzheimer’s disease.

This was a re-contact study, which—while conforming to local and national ethics requirements—involved retrospective review of the medical notes of patients who had been recruited into three previously described galantamine trials. Two of these were randomized, double-bind, placebo-controlled trials in mild-to-moderate Alzheimer’s—GAL-INT-1 and GAL-INT-2—which had been followed by optional open-label extensions (GAL-INT-3, -7, -8, and -13). The third was the galantamine-treatment arm of a comparative study with donepezil in moderate Alzheimer’s, GAL-GBR-2. For the researcher’s analysis, the data from these studies were combined and collated accordingly.

Reduced Cognitive Decline

Overall, the analyses suggest that long-term galantamine treatment for patients with Alzheimer’s is associated with a reduced decline in MMSE, compared with that predicted in the absence of treatment. Patients withdrawn from treatment experienced a subsequent deterioration in cognition, even if treated for at least one year.


The drop out data adds to the
strengths of the new study by
increasing the size of the patient
cohort and the lengthening the period
of follow-up.


The exploratory statistical model used is a valuable addition to studies of cognitive decline in patients with Alzheimer’s, precisely because it takes into account both galantamine treatment and withdrawal of therapy. The collection of retrieved dropout data made possible the evaluation of patients who had discontinued galantamine treatment, as well as those who had remained on therapy. The dropout data adds to the strengths of the new study by increasing the size of the patient cohort and the lengthening the period of follow-up.

Limitations of the Study

However, the results could be skewed because the usual limitations of data collected from clinical trials apply: patients with serious comorbidities were excluded from entering the initial studies, while those patients who were included could be deemed to have received specialist care. In addition, the study was carried out retrospectively and used unscheduled MMSE measurements collected at different time points. These weaken the analyses, as do patient attrition, creating the potential for selection bias and sample restrictions. This could result from choosing subjects because of their willingness and ability to participate. Also, no control arm was included, and therefore multivariate analyses were employed. Finally, it should be noted, with regard to the non-controlled study design, that there are important ethical issues preventing long-term use of placebo in patients with a condition for which there are four effective licensed drug therapies.

The Paucity of MMSE Progression Studies

Until now, according to the international retrospective researchers, information on progression of Alzheimer’s in terms of MMSE scores during galantamine treatment has been limited. In one 12-month randomized, controlled trial of galantamine and donepezil in patients with moderate Alzheimer’s, a greater percentage of patients receiving galantamine had stable or improved cognition (defined as change in MMSE ≥0) compared with donepezil (55% versus 33%).

In another 12-month study, untreated patients reported that 26% had stable or improved cognition in terms of MMSE. The data from these two studies—suggesting reduced decline on MMSE with long-term galantamine treatment—are consistent with previous analyses based on the present dataset (plus data from an additional study, GAL-INT-6), which found an association between time to institutionalization and duration of treatment with galantamine.

Delaying the Decline

The benefits of galantamine therapy observed in the present analysis are consistent, as well, with other MMSE data reported for long-term AChEI treatment. In the AD2000 long-term, placebo-controlled study of 565 community-resident patients with mild-to-moderate Alzheimer’s, donepezil was found to delay the decline in MMSE relative to placebo (treatment difference, 0.8 points at 2 years. The International Outcomes Survey in Dementia was a 2-year, prospective, longitudinal and observational cohort survey in 2288 patients with mild-to-moderate Alzheimer’s. As with the present study, the results indicate that decline in MMSE scores was less steep than predicted in untreated patients. Likewise, a 5-year study of rivastigmine in 1998 patients with mild-to-moderate Alzheimer’s found that MMSE deterioration was delayed in patients receiving active treatment, compared with predicted decline.

Withdrawal Precipitates Decline

The international retrospective study also showed that withdrawal from galantamine treatment resulted in a subsequent decline in cognition. This is consistent with the rapid decline observed for patients withdrawn from treatment after short-term galantamine therapy (3–5 months). Similar cognitive deterioration after donepezil cessation has also been noted. In a 15-week trial, patients with Alzheimer’s exhibited significant cognitive benefit after 12 weeks of donepezil usage, but after 3 weeks of subsequent placebo washout, although statistically significant improvement was still apparent, ADAS-Cog and MMSE scores had begun to return to baseline values.


To repeat, the international
retrospective study demonstrates both
the value of long-term galantamine
therapy and the deterioration that
occurs after treatment is
discontinued.


Then, in a somewhat longer study, showing significant cognitive benefit after 24 weeks of donepezil treatment, following 6 weeks of subsequent placebo washout, scores on all measures used to assess patients declined to values that were not statistically different from placebo. Nonetheless, data have also shown cognitive deterioration during placebo washout after 12 weeks of donepezil followed by an initial period of post-washout recovery when patients received further treatment.

In the AD2000 study, after long-term therapy (48 weeks) with donepezil, there was a 1.45 point MMSE greater decline than placebo during a 6-week washout period prior. This was despite an improvement after 12 weeks of subsequent retreatment with donepezil in which there was an improvement of 2.84 MMSE points more than the control group.

To the contrary, in a report submitted to the National Institute for Health and Clinical Excellence (NICE) in England and Wales, the Alzheimer’s Society describes the caretakers report that when the treatment is restarted patients do not reachieve their earlier functioning levels. This report argues that patients who have benefited from donepezil treatment should have continued, and that treatment should not be stopped to determine whether a patient is benefiting from therapy.

The Deterioration That Occurs After Treatment Is Discontinued

To repeat, the international retrospective study demonstrates both the value of long-term galantamine therapy and the deterioration that occurs after treatment is discontinued. Because of the extent of deterioration following discontinuation, physicians may reconsider and reinitiate AChEI therapy for those in which it has been stopped.

Once again, this study is particularly relevant in the context of current treatment and research in Alzheimer’s because many patients will have received prior AChEI therapy, or treatment with new (e.g., disease-modifying) drugs which may be adjunctive in nature.

List Making Continuation

In is important to understand that although the current study focused on galantamine, the model used could be adapted to explore long-term data generated in studies of other drugs or supplements. It could provide a benchmark that others might wish to use when considering long-term therapeutic effects. After all, what is the goal, if not to maintain ourselves over the long term and allow us to continue to create and maintain our lists, along with the probable spur to longer life?

References

  1. Kavanagh S, Van Baelen B, Schäuble B. Long-term effects of galantamine on cognitive function in Alzheimer’s disease: A large-scale international retrospective study. J Alzheimers Dis 2011 Sep 2. [Epub ahead of print]
  2. Alzheimer’s Association, 2011 Alzheimer’s Disease Facts and Figures, Alzheimer’s & Dementia 2011;7(2). http://www.alz.org/downloads/Facts_Figures_2011.pdf. Accessed September 25, 2011.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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