- Last edited on August 14, 2023
Bupropion (Wellbutrin)
Primer
Bupropion (Trade name: Wellbutrin) is an antidepressant in the norepinephrine dopamine reuptake inhibitor (NDRI) class used in the treatment of major depressive disorder and as a smoking cessation agent in tobacco use disorder (Bupropion SR [Trade name: Zyban]).
Pharmacokinetics
See also article: Introduction to Pharmacology
Pharmacokinetics of Bupropion
Absorption | T-max of about 5-6 hours for both bupropion SR and XL. Taking bupropion with food has no clinically significant effect. |
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Distribution | Protein-binding is 84% for bupropion and similar for hydroxybupropion |
Metabolism | Bupropion is rapidly and extensively metabolized in the liver by CYP 2B6 in the liver to three active metabolites, the most important of which is hydroxybupropion. |
Elimination | Renally (urine) |
Half-life | 21 hrs for bupropion SR; up to 37 hrs for active metabolite |
See also article: Cytochrome (CYP) P450 Metabolism
Bupropion: Cytochrome P450 Metabolism
Substrate of (Metabolized by) | 2B6 |
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Induces | |
Inhibits | 2D6 (potent!) |
Pharmacodynamics
Mechanism of Action
- Bupropion is structurally very similar to phenylethylamine (amphetamine and diethylpropion), which are potent stimulants
- Bupropion inhibits the re-uptake of norepinephrine (NE) and dopamine neurotransmission without any significant direct effects on serotonin neurotransmission (this makes it one of the few only non-serotonergic antidepressants)
- Bupropion also has effects on the dopamine reward pathways (blockade of neuronal re-uptake of dopamine and norepinephrine, and inhibition of nicotinic acetylcholine receptors), which makes it useful as an agent in smoking cessation.
- The major metabolite, hydroxybupropion, is present at levels 10-20 times higher than bupropion itself and blocks only NE reuptake
Toxicity
See also: Tox and Hound: Tox & Hound – Illbutrin
- In overdose: few deaths have been reported – usually through seizures (1/3 of all overdose), bradycardia, cardiac arrest
- Overdose symptoms include sinus tachycardia, hypertension, GI symptoms, hallucinations, and agitation
Indications
- Off-label as an adjunctive treatment to reverse antidepressant-induced sexual dysfunction or to augment anti-depressant efficacy in partial responders and non-responders to other medications.[1]
- For some it has been used as an attention-deficit/hyperactivity disorder treatment adjunct
Dosing and Formulations
Bupropion comes in three formulations, the most convenient form (XL) was released in 2003 that allowed for once daily dosing.[2]
Dosing and Formulations for Bupropion
Bupropion Intermediate-release (IR) | Bupropion Sustained-release (SR) | Bupropion Extended-release (XL) | |
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Tradename | Wellbutrin | Zyban | Wellbutrin XL |
Frequency | Requires TID dosing | Requires BID dosing | Once daily dosing, but pill cannot be cut, or else it loses its efficacy |
Starting Dose (Depression) | - | - | • 150 mg PO daily, then increase to 300 mg qDay on day 4. • May increase to 450 mg daily after more than 4 weeks, if no clinical improvement observed at 300 mg daily. |
Starting Dose (Smoking Cessation) | - | • Start 1-2 weeks before quitting smoking at 150mg PO qAM for 3 days • Then increase to 150mg PO BID for 7-12 weeks • Treatment can last up to 6 months. | - |
Max Dose | Wellbutrin IR 100 mg TID | Wellbutrin SR 150 mg BID | Wellbutrin XL 300 mg once daily |
Tapering | There is no discontinuation syndrome associated with bupropion. | There is no discontinuation syndrome associated with bupropion. | There is no discontinuation syndrome associated with bupropion. |
Monitoring
Contraindications
Absolute
- Seizure disorder (due to lowered seizure threshold)
- Eating disorder, (a higher incidence of seizures was found in patients treated for bulimia with bupropion IR)
- Alcohol or benzodiazepine withdrawal
- MAOi in last 14 days
- Abrupt discontinuation of ethanol or sedatives (due to lowered seizure threshold)
- Hypersensitivity in the past
Relative
- Caution is warranted in patients with a predisposition to psychosis
Drug-Drug Interactions
- Bupropion levels are increased by CYP 2B6 inhibitors
- Bupropion increases levels of CYP 2D6 substrates (e.g. - aripiprazole)
- Bupropion is often combined with venlafaxine, which may increase levels of venlafaxine (it is a 2D6 substrate)
- Carbamazepine, phenytoin, and phenobarbital all induce the metabolism of bupropion, resulting in lower bupropion levels
- May rarely cause CNS toxicity when used with lithium, including seziures
- Need to wash out MAOIs for 14 days before starting bupropion, as MAOIs increase risk of acute bupropion toxicity
- Can cause delirium with other prodopaminergic drugs
- Metoprolol may increased risk of sinus bradycardia
- Levodopa and amantadine, higher incidence of neuropsychiatric adverse effects when combined with bupropion (e.g. - confusion, agitation, delirium, tremor, ataxia, dizziness)
- Nicotine patches, combined use can increase blood pressure (need to monitor)
Side Effects
- Headache, constipation, dry mouth, insomnia, dizziness, tremor, tinnitus, agitation, nausea and vomiting, tic exacerbation (in youth) are the most common adverse events
- There can be increased blood pressure as well
- 10-29% experience insomnia, dry mouth, nausea, constipation
- Among the newer antidepressants, bupropion has the lowest incidence of sexual dysfunction, weight gain, and somnolence (<10% sexual side effects)
- For those with severe anxiety or panic disorder, bupropion is a bad choice: up to 50% of people can get worsening anxiety!
- So don't use as first line for depression with anxious features, or if you suspect anxiety
- Less likely to precipitate mania in bipolar I than tricyclics
Adverse Events
- Bupropion can cause in rare cases hallucinations, delusions, catatonia, delirium, word-finding difficulties, memory impairment
- Bupropion-associated delayed onset urticaria (rashes) have been reported in the literature.[5]
- In most of these cases, patients improve after discontinuing the medication, and could undergo a rechallenge of bupropion at lower doses.
- Even rarer, case reports of true anaphylactic reactions have been reported.[6]
Seizures
- Seizures are associated with bupropion but are reported rarely.
- Under 300 mg a day, the risk is 0.05% (about the same as other antidepressants), but doses over 450 mg, the risk of seizures increases to 0.4%.[7]
- Risk factors include: history of seizures, alcohol use disorder, benzodiazepine withdrawal history, central nervous system diseases, head trauma, and epileptiform discharges on EEG.
Clinical Pearls
- Bupropion's potent CYP 2D6 antagonism is often forgotten by clinicians!
- There is no discontinuation syndrome (or very small risk) in bupropion.
- If insomnia is marked, take the afternoon dose earlier in the afternoon, but at least 8 hours after the first daily dose
- Unlike most other antidepressants, bupropion does not suppress REM sleep.
- Bupropion is relatively weight neutral
- Since it is structurally very similar to stimulants, bupropion can have abuse potential when crushed, injected intravenously, or snorted.
- Bupropion is one of the few antidepressants that is thought to have a lower risk for open-angle glaucoma.[10]
- SSRIs are associated with a risk for glaucoma.[11]
Special Populations
Geriatric
See main article: Geriatric Pharmacology
Pediatric
See main article: Pediatric Pharmacology
Obstetric and Fetal
See main article: Obstetric and Fetal Pharmacology
Medically Ill
See main article: Psychotropic Dosing in the Medically Ill
Resources
Contrarian Views
References
1)
Fava M, Rush AJ, Thase ME, et al. 15 Years of Clinical Experience With Bupropion HCl: From Bupropion to Bupropion SR to Bupropion XL. Primary Care Companion to The Journal of Clinical Psychiatry. 2005;7(3):106-113.
2)
Fava, M., Rush, A. J., Thase, M. E., Clayton, A., Stahl, S. M., Pradko, J. F., & Johnston, J. A. (2005). 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Primary care companion to the Journal of clinical psychiatry, 7(3), 106.
3)
Kumar, S., Kodela, S., Detweiler, J. G., Kim, K. Y., & Detweiler, M. B. (2011). Bupropion-induced psychosis: folklore or a fact? A systematic review of the literature. General hospital psychiatry, 33(6), 612-617.
4)
Howard, W. T., & Warnock, J. K. (1999). Bupropion-induced psychosis. American Journal of Psychiatry, 156(12), 2017-a.
5)
Hu, L. Y., Liu, C. J., Lu, T., Hu, T. M., Tsai, C. F., Hu, Y. W., ... & Su, T. P. (2013). Delayed onset urticaria in depressive patients with bupropion prescription: a nationwide population-based study. PloS one, 8(11), e80064.
6)
Risma, C. J., Pazderka, M. J., Chong, Y. J., & Sharma, A. (2015). Bupropion-induced delayed-onset anaphylaxis. The primary care companion for CNS disorders, 17(3).
8)
Castro, V. M., Clements, C. C., Murphy, S. N., Gainer, V. S., Fava, M., Weilburg, J. B., ... & Smoller, J. W. (2013). QT interval and antidepressant use: a cross sectional study of electronic health records. Bmj, 346, f288.
9)
Teply, R. M., Packard, K. A., White, N. D., Hilleman, D. E., & DiNicolantonio, J. J. (2016). Treatment of depression in patients with concomitant cardiac disease. Progress in cardiovascular diseases, 58(5), 514-528.