Table of Contents

Drug of the Month:  
Bupropion (Wellbutrin)

Surprise: It's just another (mild) amphetamine

Bupropion chemical structure

This drug has been with us over 25 years now, yet it is still misunderstood. Bupropion was introduced to the US market in 1988, before fluoxetine (Prozac), believe it or not. It was the first of the new generation of post-tricyclic antidepressants; instead of becoming the blockbuster that would be Prozac, it had some bad luck. A few cases of seizures occurred in patients hospitalized at McLean Hospital, and the makers of Prozac used those cases to beat bupropion into submission. Clinicians turned to the new post-TCA agents mainly for safety reasons, not having to worry about overdose toxicity or cardiac arrhythmias.  Prozac opened the way for the antidepressant era as other SRIs quickly followed in the early 1990s.  For a number of years, clinicians didn't realize that SRIs produced sexual dysfunction, and by the time they found out, the use of SRIs had already become well-established.  

Two decades later, after all these agents became generic and the pharmaceutical marketing wars had ended, clinicians can look at these agents more objectively, and bupropion is making a comeback. We now know more about its benefits:  no sexual dysfunction (in fact it enhances sexual drive); weight loss; and reduction of seizure risk with the slow release formulation (Wellbutrin SR, which is now generic in the US; the seizure rate is 0.1% with Wellbutrin SR, which is equivalent to SRIs, as opposed to 0.4% with immediate release bupropion.) Some studies also find low manic switch rates.

Bupropion is hot again, too late for its makers to make profits, but not too late to impact many patients. But what many clinicians don't realize is what bupropion is. If you ask most clinicians and researchers about its mechanisms, they will say it has mild dopamine agonism (or maybe also mild norepinephrine agonism).  Okay, but what kind of drug is it?  It usually isn't included in any drug class.  It isn't one of the SRIs.  How does it produce its mild dopamine/norepinephrine agonism? 

This mystery shouldn't have persisted for two decades. The solution to the saga of bupropion is: It's just another amphetamine, as is visible in its chemical structure.  No wonder it enhances libido and leads to weight loss!

Clinical efficacy and inefficacy

It's just as important to know when a drug doesn't work as when it works. Thus, as noted in the Fast Facts box, clinicians should realize that bupropion has been proven ineffective in bipolar depression, in contrast to unipolar depression (major depressive disorder). In bipolar depression, bupropion was equivalent to placebo, when added to standard mood stabilizers (G Sachs et al, NEJM, 2007, 356:1711-22). In other words it did not improve depression at all. Many researchers emphasize the fact that bupropion did not cause mania more than placebo in that study either, but this is not a justification to use a drug that provides no clinical benefits for depressive symptoms in bipolar illness. Further, although the medium  doses  used  there  did  not  cause  more mania  than  placebo,  this  does  not  mean that bupropion will never cause mania. In fact, like all antidepressants, it can cause mania at a high enough dose.   In some who are sensitive to it, bupropion will cause mania even at low doses.

Fast Facts: Bupropion

  1. Typical effective dose: 100-300 mg/d (SR formulation, maximum 400 mg/d)
  2. Biological mechanism: Mild dopamine/norepinephrine agonism
  3. Typical side effects: Anxiety, insomnia
  4. Less common but important side effects: Mania, seizures
  5. Clinically proven efficacy: mild/moderate unipolar depressive episodes
  6. Clinically proven inefficacy: bipolar depression
  7. Other proven uses: weight loss, sexual dysfunction, smoking cessation

Biological mechanism

This mild dopamine agonism, it should be noted, is less than occurs with sertraline (E Richelson, Mayo Clin Proc, 2001, 76:511-527). This may be why bupropion has avoided being labeled a controlled substance. Yet the drug is still a street drug of value, often ground up and snorted for its addictive properties. The PL impression is that for severe depressive illness of any variety, bupropion is a rather ineffective agent.

The PL Bottom Line

  • Bupropion is a mild amphetamine
  • It is not effective in bipolar depression
  • It does not seem effective in severe depression of any kind
  • Its many benefits are amphetamine-like, and it is abused by some persons

Meet our expert EDITORIAL BOARD, composed of clinicians and researchers from around the world. 

Subscribe to the RSS feed below to follow our "What's new" blog posts