Deprenyl and Alzheimer’s disease—update
By Ward Dean, M.D.
Deprenyl (aka seligiline, trade names Eldepryl®, Jumex®) was discovered in Hungary in the 1950s and was patented by Professor Jozsef Knoll of Semmelweis University in Hungary in 1962. Deprenyl was shown to extend maximum lifespan in animals, enhance cognition in normal healthy animals, reduce the symptoms and delay the progress of Parkinson’s and Alzheimer’s disease and act as an aphrodisiac and performance-enhancer in male animals and men.
In our book, Smart Drugs II, the Next Generation (1993), based on a number of positive studies, we wrote that deprenyl appeared to be a powerful weapon against Alzheimer's disease.1 At about that same time, Professor Knoll recommendedthat; “Alzheimer’sdisease patients need to be treated daily with 10 mg deprenyl from diagnosis until death." 2 Curiously, research on selegiline peaked ten years after the publication of our book and plummeted thereafter. What happened, I wondered, to the interest in what I still believe to be an effective antiaging, cognitive-enhancing substance?
Cochrane Review Meta-Analyses Slams Deprenyl’s Value as Alzheimer’s Drug
From 2000-2003, a series of articles critically reviewed deprenyl’s efficacy in Alzheimer’s disease—two in Cochrane Reviews,3,4 and one in International Journal of Geriatric Psychiatry.5 Cochrane Reviews is considered the “gold Standard” for “meta analyses,” in which the authors critically analyze a number of double-blind controlled studies to arrive at a consensus of “evidence-based medicine.” All three of these meta-analyses relied on the same statistician, reviewed essentially the same studies and arrived at progressively more negative conclusions in each review.
The first Cochrane Review conceded that of the 17 trials considered, 14 trials reported beneficial effects of deprenyl in the treatment of cognitive deficits, and 3 reported improvements in behavior and mood. Pooled data for all cognitive tests suggested significant benefits with deprenyl compared to controls. Two years later, a follow-up report by the same statistician (Birks)--but with different co-authors—again reported that overall, the studies indicated that deprenyl -users demonstrated improved cognition at 4-6 and 8-17 weeks. But the following year in 2003, the authors of the first Cochrane Review issued a blisteringly negative third meta-analysis.5
In this third review, the authors again positively reported that; “the meta-analysis revealed benefits on memory function shown by improvement from several cognitive tests,”6-18 and “The combined memory tests, and overall combined cognitive tests…showed an improvement due to deprenylcompared with placebo at 4-6 weeks and 8-17 weeks.” [Emphasis added] In addition, in “several studies [which] assessed activities of daily living using several different scales,6,9,11,12,14,15 “the combined tests showed an improvement due to deprenyl at 4-6 weeks.”5
Inexplicably, the reviewers then concluded paradoxically and without apparent justification that “Despite its initial promise, i.e. the potential neuroprotective properties, and its role in the treatment of Parkinson's disease, deprenyl for Alzheimer's disease has proved disappointing. There would seem to be no justification, therefore, to use it in the treatment of people with Alzheimer's disease, nor for any further studies of its efficacy in Alzheimer's disease.”5
With that disparaging conclusion, further research into the use of deprenyl for Alzheimer’s use ground to a screeching halt (Fig. 1). Another understandable reason for the fall-off in published studies about deprenyl is that brand-name protection for Eldepryl® (selegiline) in the U.S. had ended, and there was little likelihood for pharmaceutical-sponsorship of further trials.
Figure 1: Time-line of selegiline studies.19 Note the dramatic drop in annual studies following the publication of the disparaging meta-analyses.
Analysis of the Meta-Analyses--Review of the Reviewers
I was thunder-struck by the negative conclusions reached by the Cochrane Reviewers, which seemed to fly in the face of the positive clinical studies that we had reviewed in SDII—and, for that matter, which were included in the Cochrane Reviews. Admittedly, Alzheimer’s disease is a chronic debilitating disease, that results in progressive death of brain cells, for which there is no known definitive cure. Deprenyl is not the “silver bullet” for Alzheimer’s disease that we all hope for—but it has been shown to delay neurodegeneration, and restore the catecholamine balance in brains altered by Alzheimer’s disease. Certainly, any treatment that slows or reverses this debilitating disease to any degree, with minimal or no adverse side effects, is a welcome addition to our therapeutic armamentarium.
I re-examined the 17 studies in the meta-analysis, as well as the studies which were specifically not included--as well as a major study that had not previously been considered (but which should have been)—to determine the credibility of the meta-analyses.
Of the papers included in the reviews, most reported positive results to varying degrees. Unless otherwise noted, the studies were all double-blind, placebo-controlled trials with Alzheimer’s patients, using 5 mg deprenyl twice daily. Here, in summary, are the outcomes of the positive studies I could find (several were obscure and unavailable):
Thus, at least 10 of the 17 studies showed apparent benefit from deprenyl in Alzheimer’s patients. Although 5 studies did not find any benefit from deprenyl, there were no adverse effects.
Deprenyl Studies excluded from the Meta-Analysis
The Cochrane Review authors also considered but excluded an additional 16 studies, for various reasons. Of these studies which reported positive results:
Comparisons and Combination Therapy--Deprenyl vs (or combined with) other Cognitive Enhancers
Largest, Most Positive Study Ignored by Meta-Analyzers
Figure 2: Improvement in SCAG short term memory scale with deprenyl (solid line) compared to placebo (broken line).32
Conclusion
Unfortunately, Alzheimer’s Disease is presently an incurable neurodegenerative disease. Although a number of treatments are used to minimize or improve the symptoms, there is no proven treatment to reverse its downward course. By the time the diagnosis is made, the patients are usually past complete recovery, since the neuropathological changes in the affected neurons are on an irreversible downward path.
Since Alzheimer’s disease is believed to be a byproduct of “normal” brain aging, our best hope to significantly decrease its prevalence is to slow the natural aging of the threatened neurons by administering a protective substance like deprenyl. Although deprenyl does not alter the landmark pathological changes of Alzheimer’s once they have become manifest (such as neurofibrillary tangles, amyloid beta or abnormal tau proteins), it has demonstrated over and over via multiple mechanisms that it can slow the progression of Alzheimer’s disease, and in many cases enhance cognitive and behavioral indices of the disease. Therefore, the optimum time to use selegiline is before the disease presents.
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