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Bupropion is one of the better tolerated antidepressants, but concerns about anxiety, insomnia, and seizures have dampened its popularity. In this podcast, we’ll see how well those concerns hold up to the evidence.
Bupropion ranks fourth in the more frequently prescribed antidepressants, and has always lagged behind the serotonin agents (SSRIs and SNRIs) in popularity. The reason may have more to do with a few myths about bupropion than the actual evidence.
Why does this matter?
Bupropion lacks many of the side effects that can hinder adherence to SSRIs: sexual side effects, weight gain, apathy, sedation, and withdrawal problems.
A little history
Bupropion was the first modern, or “second generation” antidepressant, to enter the market, but it entered the scene in the worst sort of way. Released in 1985, it soon became associated with an alarming rate of seizures, particularly in patients with bulimia. It was withdrawn from the market soon after, and rereleased in 1989 with a lower maximum dosage: 450 mg per day instead of 600mg per day. By that time, Prozac (fluoxetine) had already come out in 1987 and was rapidly becoming one of the biggest blockbusters in psychiatry. Bupropion had lost ground, and never regained it.
Myth #1: Bupropion is the antidepressant with the highest risk of seizures
No. It’s likely that the instant release version does, because the risk is dose-dependent so when it’s dosed three times a day patients might accidentally take their tablets too close together, raising the blood level and the seizure risk. With the SR, XL, Aplenzin, and Forfivo varieties, the risk of seizures has gone down. In a meta-analysis of 164 articles from 2018, it was clomipramine that came out with the highest seizure risk, and bupropion was not even at the top.1 A separate study from 2018 of over 5,000 elderly patients with new onset seizures found that escitalopram (Lexapro) and citalopram (Celexa) had the highest seizure risk, while the risk for bupropion was about the same as the other antidepressants they looked at.2
Myth #2: Bupropion can cause anxiety
Yes it can, but the rate of anxiety as a side effect to bupropion are about the same as that of other antidepressants, according to several analyses of controlled FDA-registration trials.3 All antidepressants can cause anxiety, and they do in about 1 in 10 depressed patients. Likewise, the risk of “agitation” with bupropion is similar to that with other second-generation antidepressants.
I’ve found that this risk is significantly improved when I dose bupropion low and slow in patients with anxiety. Using the instant release bupropion, I’ll start at 75 mg per day and raise the daily dosage by 75 mg each week until I reach the target dose, and then switch to an extended-release version. I also use this strategy when starting bupropion in a patient with bipolar depression. Although I try to avoid antidepressants in that population bupropion does have a lower risk of causing manic switches.
Myth #3: Bupropion won’t help anxiety in depressed patients
I have reason to doubt this one. In a meta-analysis of 10 randomized controlled trials of depression with anxiety, outcomes for anxiety were not significantly different between bupoprion and the SSRIs, including several large trials where it was compared head-to-head with an SSRI.4 Now, there is a slight twist in this story. The same authors of that paper reanalyzed the data looking specifically at patients with very high levels of anxiety. In that subgroup, the SSRIs had a slight advantage, but the authors concluded that you’d need to treat 17 patients with a highly anxious depression with an SSRI in order to see one benefit over bupropion.5 That’s a lot of patients who might lose their sex drive for a slight advantage.
Those studies were done in patients with anxious depression, but what about patients with a separate anxiety disorder. Here bupropion may not fare as well, unless that anxiety disorder is the generalized type (GAD). In GAD, bupropion performed just as well as escitalopram (Lexapro) in a small head-to-head controlled trial.6 However, bupropion has failed in very small trials of panic disorder, post traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD).
Another Myth (#4): Bupropion isn’t a good fit for patients with insomnia
This one is partly true. Bupropion (along with desvenlafaxine) does carry a higher risk of causing initiation insomnia than the other antidepressants, but the difference is very small. Most second-generation antidepressants can cause insomnia, and the rates are similar.7 However, sleep quality is a different matter, and here bupropion shines. Depression impairs sleep architecture in several ways. There is more REM latency (the patient enters REM too quickly), REM density, and less of the restorative slow-wave sleep. Bupropion reverses those changes, while the SSRIs tend to make them worse.
It’s a paradox that the SSRIs can treat depression while worsening sleep quality.[8 ]They can also cause restless leg syndrome, something that bupropion can treat, according to a recent randomized controlled trial.[9,10]
On the other hand, bupropion does stand out among the antidepressants as having a positive effect on energy.11 When patients are up and active during the day, they are likely to sleep better at night. To me, activity level is a much more important outcome in depression than the amount of time it takes to fall asleep, so I won’t shy from choosing bupropion in a patient with insomnia.
Dr Aiken is Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine and the Director of the Mood Treatment Center in Winston-Salem, NC. He is Editor in Chief of The Carlat Psychiatry Reportand Section Editor for Psychiatric Times.
Dr Aiken does not accept honoraria from pharmaceutical companies but receives royalties from W.W. Norton & Co. for a book he co-authored with James Phelps, MD, Bipolar, Not So Much.
1. Steinert T, FrÃ¶scher W. Epileptic Seizures Under Antidepressive Drug Treatment: Systematic Review. Pharmacopsychiatry, 2018;51(4):121-135.
2. Finkelstein Y, Macdonald EM, Li P, et al. Second-generation anti-depressants and risk of new-onset seizures in the elderly. Clin Toxicol (Phila), 2018;56(12):1179-1184.
3. Zimmerman M, Posternak MA, Attiullah N, et al. Why isn't bupropion the most frequently prescribed antidepressant? J Clin Psychiatry 2005;66(5):603-610.
4. Papakostas GI, Trivedi MH, Alpert JE, et al. Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of anxiety symptoms in major depressive disorder: a meta-analysis of individual patient data from 10 double-blind, randomized clinical trials. J Psychiatr Res, 2008;42(2):134-140.
5. Papakostas GI, Stahl SM, Krishen A, et al. Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies. J Clin Psychiatry, 2008;69(8):1287-1292.
6. Bystritsky A, Kerwin L, Feusner JD, et al. A pilot controlled trial of bupropion XL versus escitalopram in generalized anxiety disorder. Psychopharmacol Bull, 2008;41:46-51.
7. Ott GE, Rao U, Lin KM, et al. Effect of treatment with bupropion on EEG sleep: relationship to antidepressant response. Int J Neuropsychopharmacol. 2004;7:275-281.
8. Mayers AG, Baldwin DS. Antidepressants and their effect on sleep. Hum Psychopharmacol. 2005;20:533-559.
9. Rottach KG, Schaner BM, Kirch MH, et al. Restless legs syndrome as side effect of second generation antidepressants. J Psychiatr Res. 2008;43:70-75.
10. Bayard M, Bailey B, Acharya D, et al. Bupropion and restless legs syndrome: a randomized controlled trial. J Am Board Fam Med. 2011;24:422-428.
11. Alberti S, Chiesa A, Andrisano C, et al. Insomnia and somnolence associated with second-generation antidepressants during the treatment of major depression: a meta-analysis. J Clin Psychopharmacol, 2015;35(3):296-303.