Bupropion

I teach how to read meta-analysis articles

Welcome to the Frontier Psychiatrists. It’s a newsletter. Today, you will learn things about science. There is a paywall. It’s an experiment. Plenty of good stuff before it! I have “get past the paywall for sharing” turned on, so it doesn’t have to cost you money. Other excellent (if weird) reviews in the series include:

Effexor, Buspar, Risperdal, Zyprexa, Neurontin, Xanax, Klonopin, Paxil, Prozac, Clozaril, Lamictal, Lithium, Latuda, Ambien, and generally Benzos, specifically maybe Benzos leading to death by suicide, Geodon, Zoloft, Auvelity, and over 500 articles total in this newsletter thus far. You should subscribe!

Bupropion — the most renamed antidepressant. I could go back and check that claim, but I'm not going to. Because it's a waste of everyone's time. Here are the different ways in which you can get that medication as brand name pill, alone or combined with other medicines:

Wellbutrin — depression

Wellbutrin, sustained release (SR)

Wellbutrin, extended-release (XL)

Zyban — smoking cessation.

Contrave (in combination with naltrexone) — weight loss.

Auvelity (in combination with Dextromethorphan) — depression

Aplenzin (the hydrobromide salt instead of the hydrochloride salt for Wellbutrin) — depression and smoking cessation…and a super-cringe-worthy sponsored Google ad when I searched just now).

“Real Talk with Aplenzin” is the worst show on HBO ever.

Forfivo XL (this is the 450 mg version of the hydrochloride salts in one pill…instead of different pills). — depression

I kind of like saying “hydrobromide salt.”

The original FDA approval was in 1985. “On-label?” The drug is FDA-approved for (adult) depression, seasonal affective disorder, and smoking cessation. Common Off-label, non-FDA-approved uses include anti-depressant-induced sexual dysfunction—this “use case” was promoted illegally and led to $3,000,000,000 in fines in 2002, attention-deficit/hyperactivity disorder (ADHD), depression associated with bipolar disorder, and obesity. In pediatrics, bupropion has data for ADHD.

The original patent for this odd duck of a drug was issued in 1974 to what was at the time Burroughs Wellcome—that is where the Wellbutrin must have come from!?— which is now a part of the (massive) GlaxoSmithKline¹.

I call it an odd duck because unlike most antidepressant meds, which include the serotonin system in their mechanism of action, Wellbutrin does not. It predominantly leads to more dopamine and, to a lesser extent, norepinephrine, hanging out in synapses thanks to the prevention of “reuptake” by the presynaptic terminal. This means no sexual side effects.². There may be a risk of increased libido, which matters when treating sex offenders or paraphilias in the wrong direction.³

This “reuptake inhibitor” mechanism has been a goldmine for pharma and a lame class of meds (according to me) since Eli Lilly leaned into it…HARD…with Prozac and its “selective” serotonin reuptake mechanism of action branding, which, as I’ve addressed previously, is nonsense⁴. The “missing” documentation of these medicines' impacts on suicidality is also an issue of some importance that I will touch on.⁵

Instead of just doing my standard drug review, I will use the bupropion data on depression to teach you. It's time for “how anyone can do a meta-analysis analysis.”

Bupropion is better than placebo in more than one study:

Welcome to the forest plot …for those not reading science all day! The way to read these (which are used in meta-analysis papers on the regular) is as follows:

Each study is usually listed on the left by author and year….

The 95% interval indicates where we are at the actual answer, which is where the square is. The wider those error bars, the less confident we are about the real underlying value compared to what the Study found.

Also, I will use a different font to make this point hit home:

So, that line in the middle, in this illustration, is a relative risk of one, which is no relative risk difference. One multiplied by any number equals that number, so a relative risk of one means no change in risk. This line can meet many different things, but it's the equipoise line where things are not different.

Again, we have those error bars, and they tell us that if they cross the vertical line, that did not have a statistically significant finding. The point of a meta-analysis of all these studies, however, is to give us some different information than an individual study.

The diamond and the bottom is the most important, and the shape of the diamond is how wide the confidence interval is.

Now, we are fully equipped to answer the question for ourselves as readers: does the diamond cross the vertical line? If so, pooled data says no difference. If not, there is a difference!

Back to bupropion! Let’s it our new skills to work?

So…

In this meta-analysis, bupropion beats placebo for depression. The studies have a large effect size, with an overall effect size of about two (!). Keep in mind, however, that this is the first episode of depression, not treatment-resistant depression. This is when you take bupropion as the very first pill you ever take. That number is also based on response rates, not remission. It's a large effect size for making your depression better, which is different from making your depression over.⁶

Suppose we want to ensure we got our meta-analysis forest plot skills down? In that case, we can look at another minute analysis, where bupropion is compared to venlafaxine— Effexor, a drug I previously wrote about! Which one is better?

Crosses the vertical line: no difference in “relative risk for clinical response rates”…yawn.

For remission? No difference. It crosses the vertical line! Yawn!

For the question, everyone is asking why no one is asking (“means change on some rating scale, even I have never heard of”)? IT STILL CROSSES THE VERTICAL LINE. No difference. Tripple Yawn.

Venlafaxine is not different from bupropion across any measure. This paper pools the three studies that compared them. No difference. You just read that like a pro! Go, team, who can now scan science papers efficiently!

That is my review for the day.

1. The market cap as of 2/7/24 is 85.83 billion.

2. Berigan TR. Possible Sexual Dysfunction Associated With Bupropion for Smoking Cessation: A Case Report. Prim Care Companion J Clin Psychiatry. 1999 Dec;1(6):193. doi: 10.4088/pcc.v01n0608. PMID: 15014673; PMCID: PMC181094.

3. Yasin W, Ahmed SI, Gouthro RV. Does Bupropion Impact More than Mood? A Case Report and Review of the Literature. Cureus. 2019 Mar 19;11(3):e4277. doi: 10.7759/cureus.4277. PMID: 31157138; PMCID: PMC6529042.

4. Jaggar M, Banerjee T, Weisstaub N, Gingrich JA, Vaidya VA. 5-HT_2Areceptor loss does not alter acute fluoxetine-induced anxiety and exhibit sex-dependent regulation of cortical immediate early gene expression. Neuronal Signal. 2019 Feb 1;3(1):NS20180205. doi: 10.1042/NS20180205. PMID: 32714597; PMCID: PMC7363295.

5. Lenzer J. FDA to review "missing" drug company documents. BMJ. 2005 Jan 1;330(7481):7. doi: 10.1136/bmj.330.7481.7. PMID: 15626785; PMCID: PMC539828.

6. Maneeton, N., Maneeton, B., Eurviriyanukul, K., & Srisurapanont, M. (2013). Efficacy, tolerability, and acceptability of bupropion for major depressive disorder: a meta-analysis of randomized–controlled trials comparison with venlafaxine. Drug design, development and therapy, 1053-1062.