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Prozac vs. WellbutrinHow do newer antidepressants work?

By Brendan I. Koerner
Posted Tuesday, March 23, 2004, at 5:23 PM ET

The Food and Drug Administration has asked pharmaceutical companies to revise the warning labels that accompany 10 popular antidepressants, in order to alert consumers to the possible risk of suicide. According to the Los Angeles Times, seven of the 10 affected drugs—Prozac, Zoloft, Paxil, Luvox, Celexa, Lexapro, and Effexor—are classified as serotonin reuptake inhibitors. How do the other three medications—Wellbutrin, Serzone, and Remeron—differ?

The oddballs, often referred to as "atypical antidepressants," target multiple receptors in the brain, while older selective serotonin reuptake inhibitors like Prozac and Zoloft focus on a single target. And contrary to the Times rundown, most pharmacologists consider Effexor a member of the multiple-receptor group, rather than a traditional SSRI.

The SSRIs work by slowing the brain's absorption of serotonin, a neurotransmitter that helps control mood. Serotonin is attracted to receptors within the brain, and those receptors contain enzymes that break down—or "reuptake"—the mood-regulating chemical. SSRIs inhibit the action of those enzymes, so a person taking such a drug experiences a resultant rise in their serotonin levels.

But serotonin is not the only brain chemical that plays a role in mental well-being. Neurochemistry researchers believe that a lack of dopamine or norepinephrine (also known as norardrenaline) also contributes to depression. So, many of the newer atypical antidepressants, which hit the market after the SSRIs debuted in the late 1980s and early 1990s, work to heighten the brain's supply of dopamine or norepinephrine.

Take Wellbutrin, the brand name for GlaxoSmithKline's bupropion. Though the drug's mechanism of action isn't entirely understood, it's generally believed to inhibit strongly the reuptake of norepinephrine and to inhibit more modestly the absorption of dopamine. Remeron (mirtazapine), meanwhile, stimulates certain nerves to release more norepinephrine, in addition to blocking certain serotonin receptors. Effexor (venlafaxine) is often characterized as a serotonin-norepinephrine reuptake inhibitor, since it stalls the brain's absorption of both neurotransmitters.

Serzone (nefazodone) is similar to the SSRIs in that it primarily affects serotonin levels (although it may impact norepinephrine, too). But it's considered more powerful, in that it not only inhibits serotonin reuptake, but completely blocks a serotonin receptor known as 5-HT2A.

"Powerful" doesn't necessarily imply greater efficacy, however, and many patients will still respond better to SSRIs than atypical antidepressants. Side effects are a key consideration for doctors and vary greatly from person to person. Serzone, for example, is reputed to cause fewer incidents of sexual dysfunction and insomnia than SSRIs. But the drug is also known to cause liver problems in some patients. Wellbutrin is also believed to cause fewer sexual side effects than its SSRI predecessors, but it can also cause uncomfortable nervousness, especially early in the treatment cycle.

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Brendan I. Koerner is a contributing editor at Wired and a columnist for Gizmodo. His first book, Now the Hell Will Start, will be published by Penguin Press in May 2008.
Photograph of the MRI brain scan on Slate's home page by Royalty-Free/Corbis.
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