Hopes for deprenyl were raised in 1985 when Austrian researcher, W. Birkmayer, found (in a retrospective study) that Parkinson's patients receiving both L-Dopa and deprenyl lived 30% longer than patients receiving L-Dopa alone.8 In the next couple of years, multi-center trials with deprenyl were started in the U.S., England and Italy. The largest of these trials was the double-blind, placebo-controlled DATATOP study in the U.S (and Canada), which tested deprenyl and vitamin E in 800 early-stage Parkinson's patients. Its main objective was to see how long it would take before the patients became impaired enough to require L-Dopa.
The medical community was electrified in 1989 when the DATATOP trial was cut short because of dramatic benefits in the patients receiving deprenyl. A few months later, a paper in the New England Journal of Medicine reported a 9-month delay before L-Dopa was necessary in the deprenyl patients. DATATOP scientists hypothesized that deprenyl might slow the progression of Parkinson's disease by slowing down the loss of dopaminergic neurons.
FDA approval of deprenyl as a treatment for Parkinson's disease soon followed, and deprenyl soon became the drug of choice for early-stage Parkinson's disease patients.
Proposed Mechanisms Of Action
Deprenyl is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B), the enzyme that degrades dopamine. Since the depletion of dopamine is the primary factor in the genesis of Parkinson's disease, and levels of MAO-B increase with advancing age in humans, 11 it is assumed that the effect of deprenyl therapy is to conserve dopamine in the brain.
Scientists speculated that deprenyl may protect brain cells from damage in Parkinson's patients through its action as an MAO-B inhibitor, or by countering the deleterious effects of free radical damage caused by dopamine metabolism and other factors.12
In the early 1990s, scientists at the University of Toronto found that deprenyl could "rescue" dopaminergic (and other) neurons from functional damage in tissue culture.13-15 Since this effect occurred at doses of deprenyl lower than those needed to inhibit MAO-B, it was suggested that there may be another mechanism of action that enables deprenyl to protect neurons in the brain.15
When the results of other clinical trials with deprenyl showed significant benefits for Parkinson's patients16 and Alzheimer's patients, it was assumed that deprenyl is an effective treatment for Parkinson's disease, that the drug might be effective for other neurodegenerative diseases, and that it might retard aging by slowing the loss of essential neurons in the brain.
The Findings Of The British Study
These assumptions must now be re-evaluated in light of the recent BMJ and AN papers.
The BMJ study investigated the effect of three treatment regimens: L-Dopa alone, L-Dopa and deprenyl, and bromocriptine (a dopamine agonist). The BMJ paper deals primarily with the first two regimens. The treatment groups were similar with respect to age, sex, duration of Parkinson's disease, and baseline disability scores.
The study was conducted by 58 physicians at 93 hospital throughout the United Kingdom. Patients were recruited between September 1985 and September 1990 at University College Hospitals and randomly assigned to the three groups. The doctors treating the patients in both L-Dopa groups determined what they considered the optimal dose of L-Dopa for each patient, which was given daily in three divided doses after meals. Deprenyl was given twice daily in 5-mg doses.
Mortality and disability scores were assessed at the beginning of the trial and every 3 to 4 months thereafter, preferably in the presence of one of the patients' close relatives. The severity of adverse side effects were rated on a scale of 0-3 at each visit.
Results Of Study
Analysis was performed in 520 patients in both groups, regardless of whether they were subsequently withdrawn from treatment. The dose of L-Dopa was increased gradually in both groups as the patients' condition worsened. After a year, the median dose of L-Dopa in the first group (L-Dopa alone) was 375 mg per day, while the median dose in the second group (L-Dopa plus deprenyl) was 375 mg After four years, the median dose of L-Dopa in group one rose to 625 mg per day, but remained at 375 mg per day in the second group.
The primary finding in The British Study, after an average of 5-6 years of follow-up, was that mortality was about 60% higher in patients given both L-Dopa and deprenyl than in those given L-Dopa alone, and that this effect was independent of sex and age. This finding was essentially the same, regardless of whether the analysis was done for patients while they were being treated, or included the period after they (252 out of 520) withdrew from the study.
The other findings were that disability scores were slightly worse in patients receiving L-Dopa than in patients receiving both L-Dopa and deprenyl, and that severe motor complications were more frequent in patients given the combined treatment.
The British Scientists' Conclusions
The British scientists' concluded that "combined treatment with levodopa and selegiline (deprenyl) in patients with mild, previously untreated, Parkinson's disease seems to confer no detectable clinical benefit over treatment with levodopa alone. Furthermore, mortality was significantly increased in the patients given levodopa and selegiline. This is the first study to report such a finding. Analysis of mortality in other ongoing studies will be needed to see if this finding can be corroborated."
"The critical question is whether the relation between levodopa and selegiline and increased mortality is genuinely causal....The precise cause of the increased mortality... remains to be determined.
"In the meantime, the patients in arm two of our trial (levodopa and selegiline) will be advised of our results and advised to withdraw selegiline from their treatment regimens."
The Results Of The Study Are Controversial
The fact that the British study is the first to report increased mortality in Parkinson's patients receiving deprenyl, coupled with the recommendation that patients stop taking it, has led to debate among doctors, many of whom aren't yet ready to accept this recommendation for their own patients.
The March 16, 1996 issue of the British Medical Journal published eight letters in response to the Parkinson's study, some of which contested the contention that deprenyl was the cause of the excess mortality in the L-Dopa/deprenyl group.18 Some doctors pointed out flaws in the British study, others presented evidence to contradict the findings of the study, and some gave their own interpretation of the findings.
Clinical Trials Contradicting The British Study
The manufacturer of deprenyl cited a collection of findings from clinical trials with deprenyl, all of which, it was stated, contradict the extra mortality found in the British study. As they put it:
"We have gathered data from 10 controlled, long-term studies (some published, some continuing); in seven the duration of treatment was at least 3.5 years; 983 patients received selegiline alone or with levodopa, and 1093 received placebo or other antiparkinsonian drugs. The mortality was 2.8% and 3.3% respectively (Table 1).
When only data from the studies of at least 3-5 years duration were analyzed, the mortality was 5.2% for the selegiline group and 5.5% for the control group."18
The British scientists responded that the results of the combined trials are "not directly comparable" to their results because they include trials with deprenyl alone as well as deprenyl and L-Dopa. They also claimed that the mortality data in the trials with more than 3.5 years of follow-up were comparable to their mortality data, but failed to provide evidence to support this contention.