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Biotech / Medical : Sepracor-Looks very promising -- Ignore unavailable to you. Want to Upgrade?

To: Don Miller who wrote (2915)	5/23/1999 2:18:00 AM
From: George Dawson	Respond to of 10280

Don, Here are a few of my observations of the press release: 1. The "noradrenergic theory" of depression is not new, but about 30 years old now. It was the theory of depression before the "serotonergic" theory. Despite these theories, nobody knows how antidepressants work. You can confirm that by picking up any prescribing manual and it will state "the mechanism of action of antidepressant medications is unknown". 2. The noradrenergic theory has been investigated mainly by monitoring the turnover of norepinephrine and its metabolites - both before drug treatment and after drug treatment with both traditional antidepressants and SSRIs like fluoxetine. Although traditional antidepressants like tricyclic depressants are not selective norepinephrine reuptake inhibitors, they do block reuptake to some degree. In some of those studies, the metabolite patterns changed in the same direction when both SSRIs and traditional antidepressants were used - suggesting that the pattern of neurotransmitter reuptake inhibition may not be a very specific mechanism. 3. Reboxetine appears to have low activity at other brain sites that lead to unwanted side effects - however this release suggests that the adverse event rates of fluoxetine and reboxetine are similar. 4. The better efficacy of reboxetine occurred only in the comparator group that was not placebo controlled. In the placebo controlled group both reboxetine and fluoxetine had similar efficacy as measures by decreased HAM-D scores (13.4 vs 13.3). 5. I have an article written by Massana (Massana J, Reboxetine vs. fluoxetine: an overview of efficacy and tolerability. J Clin Psychiatry 1998; 59[suppl14]: 8-10. In that article he concludes that "both drugs demonstrated similar efficacy on the HAM-D, but reboxetine was superior in the treatment of severely ill patients and in terms of improving social functioning". I would see this a measure of superiority requiring further replication, particularly in view of the fact that reboxetine has been compared to standard tricyclic antidepressants and found to have similar efficacy. The measure of social function is not a standard measure used in U.S. antidepressant trials - at least I am not aware of it. The Montgomery-Asberg Depression Rating Scale was used, but those results are not given in either the article or the release. All things (including past claims of superior efficacy) considered, I think it is early to be proclaiming that Reboxetine is "Better than Prozac". I think it does point to the spectre of generic fluoxetine on the horizon. All pharmaceutical manufacturers may feel the need to demonstrate that there are clear advantages of their antidepressant over fluoxetine and other SSRIs. Health care organizations and their P & T Committees will be carefully scrutinizing the evidence, especially since the cost of antidepressants and their attempts to control utilization by removing some of them from formularies has been controversial. George D.

To: Don Miller who wrote (2915)	5/23/1999 2:38:00 AM
From: George Dawson	Respond to of 10280

Don, One last thought: I do not know the half life of reboxetine, but the half-life of fluoxetine and its metabolite norfluoxetine are sufficiently long (2 - 9 days) so that steady state may not have been reached during the dose escalation period of the study. In other words, when the decision was made to increase the dose to 40mg at the 4 week mark, the plasma levels may have not been reflective of this dose change in the next four weeks ( it was an 8 week study). Prescribing info may state: "The full antidepressant effect may be delayed until greater than or equal to 4 weeks of treatment. George D.