1 Boring Old Man

Clinical Efficacy of Reboxetine in Major Depression

by Alan F. Schatzberg, M.D.

Journal of Clinical Psychiatry. 2000 61[suppl 10]:31–38.

The past decade has witnessed the advent of selective serotonin reuptake inhibitors [SSRIs] as first-line treatments for major depression. Still, there is considerable debate as to whether these agents are as effective or as potent as the first-generation tricyclic antidepressants [TCAs] or the mixed reuptake inhibitor, venlafaxine, all of which exert considerable effect on norepinephrine [NE] reuptake. Recently, reboxetine, a selective NE reuptake inhibitor [selective NRI], has been introduced in Europe. This drug has only a minimal affinity for muscarinic acetylcholine receptors and therefore causes less dry mouth, constipation, or other such effects than do the TCAs. Reboxetine does not block serotonin reuptake or α1 receptors and, thus, does not appear to produce significant nausea, diarrhea, or hypotension. Unlike other antidepressants, reboxetine appears to be nonsedating. Data on acute and long-term clinical efficacy and safety from double-blind, placebo-controlled, and active comparator studies with reboxetine are reviewed. These studies indicate that reboxetine is significantly more effective than placebo and as effective as fluoxetine in reducing depressive symptoms. Improvements in social adjustments were reported to be more favorable with reboxetine than with fluoxetine. Further, data from controlled clinical trials have shown that the side effect profile for reboxetine is relatively benign. The clinical implications of studies on reboxetine are discussed with an eye toward understanding the potential role NE reuptake blockers may play in the treatment of patients with major depression.

From the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, Calif.

Presented at the symposium "Norepinephrine: Neurotransmitter for the Millennium," held May 15, 1999, in Washington, D.C. This symposium was held in conjunction with the 152nd annual meeting of the American Psychiatric Association and was supported by an unrestricted educational grant from Pharmacia Corporation.

hat tip to Altostrata…

• Introduction. Norepinephrine: Neurotransmitter for the Millennium. Charles B. Nemeroff
• Problems With Currently Available Antidepressants. Jane F. Gumnick and Charles B. Nemeroff
• Norepinephrine Dysfunction in Depression. Amit Anand and Dennis S. Charney
• Norepinephrine Involvement in Antidepressant Action. Alan Frazer
• Clinical Efficacy of Reboxetine in Major Depression. Alan F. Schatzberg

This is an abstract of an article in a Journal of Clinical Psychiatry Supplement from 2000 written by Dr. Alan Schatzberg, Chairman at Stanford, part of symposium chaired by Dr. Charles Nemeroff, Chairman at Emory, held at the 1999 APA meeting in Washington D.C.

The problem is that 2000 was another time. The Journal of Clinical Psychiatry was a notorious target for industry funded research, and the supplements were actually sponsored by industry and used for favorable reviews of products. 2000 was the heyday of the KOLs. There’s no way to know if this symposium actually even occurred, as cites like this were commonly used as a front for an industry friendly set of review articles like this. That these articles were written by the named authors is extremely unlikely. Remember, around this time, Nemeroff and Schatzberg signed on to a textbook financed by GSK and written by Sally Laden’s firm STI. But this particular supplement is notable because Dr. Schatzberg is promoting Roboxetine, an antidepressant that appears to have been essentially inert. This was the time when Dr. Keller and an army of others signed on to another Laden production, Paxil Study 329. Likewise, Dr. Charney was the named author of an editorial in Biological Psychiatry, also written by Ms. Laden. This was the year of the famous confrontation between Dr. Nemeroff and David Healy that lead to Healy being "un-hired" for a job in Canada because he talked about Akathisia with SSRIs.

The antidepressant reboxetine: A “headdesk” moment in science

Scientific American

By Scicurious

November 30, 2010

Every so often there comes a truly "headdesk" moment in science. A moment where you sit there, stunned by a new finding, and thinking, blankly…"OK, now what?"

For psychiatry and behavioral pharmacology, one of those moments came a few weeks ago with the findings of a meta-analysis published in the British Medical Journal [Eyding et al., 2010]. The meta-analysis showed that an antidepressant, reboxetine [marketed by Pfizer in Europe, but not in the U.S., under the names Edronax, Norebox, Prolift, Solvex, Davedax or Vestra] doesn’t work. Not only does it not work, it really doesn’t work, and it turns out that Pfizer hadn’t published data on the putative antidepressant from 74% of their patients. Some people have reported that the study found that reboxetine was even "possibly harmful," but that’s not quite true. What the study did find is that reboxetine produced more side effects [noted as "adverse events"] than placebo [as might be expected], but with no positive effects at all. While many antidepressants on the market today are not great, most are effective in around 60% of patients; reboxetine turns out to be even worse than that. It turns out that publication bias was rampant. Pfizer and Lundbeck, the two companies running the studies, didn’t publish a lot of their data, especially the data showing no effect and unfortunate side effects. A bit nefarious, that. But bad science will out…

Worst. Antidepressant. Ever.

by Neuroskeptic

15 October 2010

Reboxetine is an antidepressant. Except it’s not, because it doesn’t treat depression.This is the conclusion of a much-publicized article just out in the BMJ: Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and SSRI controlled trials.

Reboxetine was introduced to some fanfare, because its mechanism of action is unique – it’s a selective norepinephrine reuptake inhibitor [NRI], which has no effect on serotonin, unlike Prozac and other newer antidepressants… So in theory reboxetine treats depression while avoiding the side effects of other drugs, but last year, Cipriani et al in a headline-grabbing meta-analysis concluded that in fact it’s the exact opposite: reboxetine was the least effective new antidepressant, and was also one of the worst in terms of side effects. Oh dear.

And that was only based on the published data. It turns out that Pfizer, the manufacturers of reboxetine, had chosen to not publish the results of most of their clinical trials of the drug, because the data showed that it was crap. The new BMJ paper includes these unpublished results – it took an inordinate amount of time and pressure to make Pfizer agree to share them, but they eventually did – and we learn that reboxetine is:

• no more effective than a placebo at treating depression.
• less effective than SSRIs, which incidentally are better than placebo in this dataset [a bit].
• worse tolerated than most SSRIs, and much worse tolerated than placebo.

In some ways, it’s still hard for me to believe that the era of this article actually happened. It reads like a pulp fiction novel. Chairmen of Departments, future APA Presidents, people in the highest of places signing on to a pseudosymposium like this. Norepinephrine: Neurotransmitter for the Millennium, followed by some articles that debunked the previously beloved SSRIs [running out of patent soon], and ending with a glowing report for a drug they couldn’t have possibly used as it wasn’t even available in this country, a drug that was essentially worse than placebo. But it did happen. And I wish I could say it was a product of a small number of bad apples in the barrel, but the number was unfortunately bigger than small, and they influenced a large number of practitioners. The pharmaceutical companies are plenty culpable. This offering by Pfizer was little more than a ruse. But without these KOLs recommending the drugs like in this symposium?/article, they wouldn’t have made it nearly so far. Dark days, those days of wine and roses…