Posts Tagged ‘SNRI’

When Mechanism Matters

August 1st, 2013

By the late 1970s, the only antidepressant medications were the MAOIs and the TCAs. Obviously, the perceived unmet need was great.

The late 70s and early 80s brought us 3 new antidepressants: Amoxapine (Asendin and others), maprotiline (Ludiomil and others), and bupropion (Wellbutrin and others). Amoxapine’s manufacturer initially claimed it would work faster; it didn’t. There were seizures among patients in a small study of bupropion in eating-disorder patients, resulting in its withdrawal from the market. It was subsequently re-introduced with warnings about the seizure risk and remains a widely used and versatile antidepressant.

Seeking a marketing edge, maprotiline’s manufacturer focused on its presumed antidepressant mechanism—norepinephrine reuptake blockade. “When mechanism matters,” bannered the large advertisements in prominent medical journals.

How wonderful it would be if we could tell which depressed patient would benefit from which molecule. There probably are different biological anomalies underlying different patients’ depression symptoms, and someday we will be able to dissect nature along its relevant “joints.” But so far, multiple studies since the 1950s that have sought to predict antidepressant response and tailor pharmacologic treatments have come a cropper. For maprotiline, the emperor had no clothes. It had no clinical advantage over other compounds, produced a high rate of seizures, and faded from use.

Vilazodone (Viibryd) was introduced a few years back. The pre-launch hypotheses for a new medicine that would have to be priced higher than inexpensive generic antidepressants were two, based on vilazodone’s pharmacologic mechanisms: (1) it would work faster, and (2) it would have fewer sexual side effects than other serotonergic drugs. Neither hope materialized.

On July 26th, FDA approved levomilnacipran extended-release (Fetzima). It is another serotonin-norepinephrine reuptake inhibitor (SNRI)—like venlafaxine (Effexor and others), duloxetine (Cymbalta), desvenlafaxine (Pristiq), and its racemic “sister,” milnacipran (Savella). For that matter, TCAs also are SNRIs. To gain market share in a competitive field, advertising may focus on the fact that pharmacologically, levomilnacipran is a more potent norepinephrine reuptake blocker than other SNRIs. This time, will mechanism finally matter? The answer will not emerge from ad copy, promotional talks, fancy graphics of neurons, or argument. The answers will come from time-consuming, expensive clinical studies (if the manufacturer is willing to take the risk) to test the hypothesis that the new drug’s pharmacology will translate into some clinical advantage—like greater efficacy in a measureable way. We’ll see.

-Alan J. Gelenberg, M.D.
Editor, Biological Therapies in Psychiatry
Shively/Tan Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief, Journal of Clinical Psychiatry

When mechanism matters

December 13th, 2010

Maprotiline (Ludiomil) is a tetracyclic antidepressant introduced in the early 1980s. It is a norepinephrine reuptake inhibitor, which is believed to be its primary mechanism of antidepressant action. It had a particularly high incidence of seizures, which the manufacturer initially minimized. Today maprotiline is seldom prescribed.

Initial advertising for maprotiline featured the headline, “When Mechanism Matters.” Perhaps the people who wrote the ad copy were banking on the Emperor’s-New-Clothes phenomenon: doctors would be too embarrassed to admit we didn’t know when mechanism mattered in selecting an antidepressant for a depressed patient. We still don’t.

We make assumptions. SSRIs work by enhancing serotonin. SNRIs work via both serotonin and norepinephrine. MAOIs work by inhibiting MAO. Perhaps these theories are valid; perhaps not. In theory, a patient who fails to respond to one SSRI should do better with a drug with a different mechanism of action, rather than a different SSRI. But the data say otherwise.

I am convinced that, ultimately, mechanism matters. And psychiatric patients are different one from the other. Someday we will understand the unique pathophysiology that underlies abnormal thinking, feeling, and behavior. Someday we will elucidate the various etiologies that distort normal brain function in these ways. And when that time comes, we will tailor treatments to the abnormalities: targeted treatments; personalized medicine.

But until that time, let’s not become gullible to those who peddle expensive new products with thinly veiled promises that understanding the receptor or other properties of a compound translates into real-life advantages. And remember that sales people are not only the companies’ marketers and representatives, but also some of our colleagues who write and lecture. A professor of mine admonished his students to be “therapeutic skeptics—but not nihilists.” Amen.

- Alan J. Gelenberg, M.D.
Editor,
Biological Therapies in Psychiatry
Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief,
Journal of Clinical Psychiatry