Question: Enclosed is the new deprenyl brochure from Discovery of Mexico. They state that mortality was 60% higher in patients using selegiline hydrochloride than those not using it. Can you comment? ——AW

Answer: The study that the brochure is referring to was discussed in detail in the Smart Drug Update: “Recent Developments with Deprenyl” by Dr. Dean and myself [SDN v5n1]. The study in question, conducted by the Parkinson’s Disease Research Group of the United Kingdom, compared mortality data in Parkinson’s patients taking L-dopa plus deprenyl (another generic name for selegiline) to those taking L-dopa alone. Although the study did show increased mortality in the deprenyl-plus-dopa group, the data were decidedly uneven, suggesting to Dr. Dean and myself that something unusual took place during the study that was not reported in the final paper published in the New England Journal of Medicine. Exactly what happened to cause these deaths is not known, but all the excess deaths took place in a single 12-month period of the 5-6 year study! For the first 5 months of this 12-month period, the death rate in the deprenyl-plus-dopa group increased by a factor of four, then gradually decreased back to baseline by the end of the 12 months.

The illustration that appeared in the deprenyl update article (see Figure 1 below) attempted to display the significance of the year in question by “subtracting” it from the graph. This was accomplished by ignoring the deprenyl-plus-dopa curve in the one-year window and lowering the subsequent curve to a point that would have been expected if there hadn’t been a big upsurge in deaths (i.e., to the point of the extrapolation line). In this new location, the deprenyl-plus-dopa curve and dopa-only curve remain closely associated for the duration of the study. We concluded from this analysis that the statistical significance of the excess deaths in the deprenyl-plus-dopa group was entirely due to the abnormally high death rate in this one-year period of this 5-6 year study.

Such anomalous data should caution us against any quick rush to judgment about what this study means to patients. Superficial conclusions about the toxicity of selegiline with or without L-dopa are unwarranted given the anomalous nature of the mortality data and the existence of other published studies showing the opposite effect (i.e., a protective effect on mortality from deprenyl).

It is equally unwarranted to assume, as the Discovery brochure implies, that only the hydrochloride form of selegiline is somehow responsible for this increased mortality. Their specious assertion that “selegiline” and “selegiline hydrochloride” are “different chemical entities” hardly justifies their implication that the increased mortality in the PDRG study is only attributable to the selegiline hydrochloride and not selegiline (or selegiline citrate). The possibility that the hydrochloric acid salt of selegiline has special toxicity is unsupported by any evidence, real or theoretical. It’s a good thing; the natural hydrochloric acid in the human stomach converts selegiline and selegiline citrate into selegiline hydrochloride. Furthermore, selegiline hydrochloride tablets are now being compounded with citric acid, which converts some selegiline hydrochloride into selegiline citrate in the GI tract.

As the Discovery brochure correctly states, the real issues about deprenyl are about “efficacy, purity and side effects.” There are genuine differences in efficacy between the high-purity Discovery-brand liquid deprenyl citrate and standard pharmaceutical deprenyl hydrochloride products. These differences are real, and they are not explained by the specific ion — chloride or citrate — which happens to accompany the selegiline molecule. It’s my considered opinion that it will turn out to be a toxic impurity in the commercial deprenyl products that is not present in the Discovery liquid deprenyl due to 1) superior quality control in their manufacturing process, or 2) some degree of chemical instability of deprenyl in its crystalline solid form. We may never know for sure. Nobody seems interested in discussing the deeper scientific and medical implications of the anomalous PDRG data. As far as I am concerned, our analysis of this study provides an additional ethical imperative to our recommendation of Discovery liquid deprenyl over other deprenyl brands.

To better illustrate the unevenness of the mortality data for subscribers, I decided to update the original figure with death-rate curves (see Figure 2, above). The solid red line is the death-rate curve for the deprenyl-plus-dopa group, which spikes suddenly 2.4 years into the study, going from an average of 2-3 deaths per year to approximately 14 deaths per year. Although such numbers are only approximate in nature (we do not have access to the study’s raw data), they do aptly illustrate the suddenness and magnitude of the increase in death rate. The periodic oscillations of the death rate, on a one-year cycle for the deprenyl-plus-dopa group (solid red line) and near-two-year cycle for the dopa-only group (dashed dark-blue line), show relatively smooth sinusoidal shapes except the one peak at 2.4 years (red line only). There, the death-rate curve looks more like a step function, suddenly rising rapidly to a level far beyond that seen anywhere else in the study. Both the magnitude and shape of this peak are unique. These data suggest that something unusual happened two years and five months into the study, the effect of which gradually wore off during the following months.

Although the death rates for both the deprenyl-plus-dopa and dopa-only groups did increase significantly towards the end of the study, the data in the 5-6th year period is not as robust as data collected earlier in the study. Subjects were recruited over time and statistically aligned at the “zero” point. Therefore, only subjects recruited at the very beginning of the study provided data for the 5-6 year period. Therefore, the statistical significance or robustness of the data at the end of the study is much less than in the beginning or middle of the study. ——SWF