Is Bupropion Your No. 1 Antidepressant Choice?


Three reasons clinicians skip over bupropion.

©CrystalEyeStudio/ Shutterstock


“Why isn’t bupropion the most widely prescribed antidepressant?” asked Zimmerman and colleagues in 2005.1 This is still a good question. All other antidepressants have been strongly associated with weight gain.2-5 All the serotonergic antidepressants (SSRIs and SNRIs) frequently cause sexual dysfunction (at a rate of 50% to 80% with questionnaire follow-up).6,7

Discontinuation of serotonergic antidepressants requires careful tapering, which takes as long as 6 to 8 weeks and sometimes 3 months or more.8,9 This prompted Fava and colleagues to suggest, “Clinicians need to add SSRIs to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with benzodiazepines [and] barbiturates . . ..”10

Why, in the face of all these disadvantages of serotonergic antidepressants-none of which are shared by bupropion-is the latter not by far the preferred starting point when patients elect an antidepressant over (equally effective11) psychotherapy?

Three reasons providers skip over bupropion

1. Clinicians fear that bupropion will not treat co-morbid anxiety and, indeed, may make it worse.


Yet available data do not support this impression. A pooled analysis of 10 studies compared bupropion and various SRIs in the treatment of major depression.12 Response rates (> 50% reduction in Hamilton Depression Scale scores) were equal among patients with non-anxious depression.

Fortunately for our purposes here, over half of the pooled sample had anxious depression. In that subgroup, response rates to bupropion were not quite as good: 59% vs 64% for the pooled SRIs (P = .03). But note that the difference is quite small. One could say that bupropion is at least almost as good at treating anxious depression as non-anxious depression.

Tellingly, this pooled analysis included Hamilton Anxiety Scale scores before and after antidepressant treatment as well. Again, response rate was defined as > 50% reduction. If bupropion does not treat anxiety in the context of depression, or actually makes it worse, one would expect a very large difference in response rates, with SRIs far superior. Yet the difference, though statistically significant, was again quite small: 54% vs 61%, respectively (P = .03).

Got that? Bupropion produced a 50% reduction in anxiety in just over half the patients with anxious depression, almost as much as that seen with the SRIs.

2. There is concern about inducing seizures.

SRIs do not appear to lower seizure threshold, although data on this are sparse according to a recent Cochrane review13 and practitioners (including me until I wrote this) have the opposite impression.14 Depression itself is associated with a substantial increase in seizure risk relative to the general population, which complicates assessment.15

The seizure rate in patients taking immediate-release bupropion was 4/1000 (0.4%) vs 0.07% to 0.09% in the general population.16 But with sustained-release (SR) bupropion the associated seizure rate fell to 0.1%, which is indistinguishable from the upper rate in the general population.

The rate in patients taking extended-release (XL) bupropion is not known. Presumably, it should be in the range of the SR because the release is slower; however, given once daily, instead of twice daily as with the SR, the peak concentration could be higher.

There are at least 2 case reports of seizures associated with the XL version.17,18 A review of all 3 bupropion forms was dismissive of seizure risk with SR and XL, but it was prepared with assistance from the manufacturer.19

3. With bupropion, one cannot simply write a prescription and have the patient return in a month.

A week at 150 mg XL is recommended before increasing to 300 mg XL as the standard dose (450 mg is the maximum, beyond which seizure risk dramatically increases).

Is it possible that prescribers are inflicting sexual dysfunction, weight gain, and withdrawal risks on patients just to save the hassle of a 2-step dose titration? That would be a cynical conclusion. Stick with irony: bupropion is not licensed for depression in the UK, which limits access.20


Dr Phelps is Director of the Mood Disorders Program at Samaritan Mental Health in Corvallis, Ore. He is the Bipolar Disorder Section Editor for Psychiatric Times. Dr Phelps stopped accepting honoraria from pharmaceutical companies in 2008.


1. Zimmerman M, Posternak MA, Attiullah N, et al. Why isn’t bupropion the most frequently prescribed antidepressant?J Clin Psychiatry. 2005;66:603-610.
2. Blumenthal SR, Castro VM, Clements CC, et al. An electronic health records study of long-term weight gain following antidepressant use. JAMA Psychiatry. 2014;71:889-896.
3. Ravindran PP, Zang W, Renukunta S, et al. Effect of comedication of bupropion and other antidepressants on body mass index. Ther Adv Psychopharmacol. 2015;5:158-165.
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5. Arterburn D, Sofer T, Boudreau DM, et al. Long-term weight change after initiating second-generation antidepressants. J Clin Med. 2016;5(4). doi:10.3390/jcm5040048.
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11. Weitz ES, Hollon SD, Twisk J, et al. Baseline depression severity as moderator of depression outcomes between cognitive behavioral therapy vs pharmacotherapy: an individual patient data meta-analysis. JAMA Psychiatry. 2015;72:1102-1109.
12. 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;69:1287-1292.
13. Maguire MJ, Weston J, Singh J, Marson AG. Antidepressants for people with epilepsy and depression. Cochrane Database Syst Rev. 2014;12:CD010682.
14. Cotterman-Hart S. Depression in epilepsy: why aren’t we treating?Epilepsy Behav. 2010;19:419-421.
15. Hesdorffer DC, Ishihara L, Mynepalli L, et al. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurol. 2012;72:184-191.
16. Davidson J. Seizures and bupropion: a review. J Clin Psychiatry. 1989;50:256-261.
17. Rissmiller DJ, Campo T. Extended-release bupropion induced grand mal seizures. J Am Osteopath Assoc. 2007;107:441-442.
18. Rosoff DM. Another case of extended-release bupropion-induced seizure. J Am Osteopath Assoc. 2008;108:189-190.
19. Fava M, Rush AJ, Thase ME, et al. 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry. 2005;7:106-113.
20. Patel K, Allen S, Haque MN, et al. Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant. Ther Adv Psychopharmacol. 2016;6:99-144.

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