Archive for August, 2013

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