Bupropion (Zyban): risk of serotonin syndrome with use with other serotonergic drugs
Cases of serotonin syndrome have been identified in associated with bupropion, especially in overdose or when bupropion is administered with other drugs with a serotonergic effect.
Advice for healthcare professionals:
- cases of serotonin syndrome have been reported in association with bupropion and coadministration with serotonergic drugs, for example
- selective serotonin reuptake inhibitors (SSRIs)
- serotonin norepinephrine re-uptake inhibitors (SNRI)
- if concomitant prescribing with other serotonergic drugs is clinically warranted:
- do not exceed the recommended dose
- remind patients of the milder symptoms of serotonin syndrome at initiation of treatment and at any change of dose and the importance of seeking medical advice if they occur
- if serotonin syndrome is suspected, either decrease the dose of bupropion or withdraw therapy depending on the severity of the symptoms
Advice to give to patients
- if you are told you may be at risk of serotonin syndrome, be aware of symptoms, including mild signs such as nausea, vomiting, and diarrhoea or increased heart rate and agitation (see full list below) and talk to your prescriber if you experience these
- never exceed the prescribed dose of bupropion
- always read the patient information leaflet for side effects to be aware of and when to seek medical advice
Review of cases of serotonin syndrome
Bupropion (Zyban) is indicated as an aid for smoking cessation in combination with motivational support in nicotine-dependent patients. It is also authorised in combination with naltrexone (Mysimba▼) as an adjunct to a reduced-calorie diet and increased physical activity for the management of weight in adults with obesity or who are overweight with co-morbidities.
A recent European review of safety data for Zyban identified at least 8 cases of serotonin syndrome, a potentially life-threatening condition, where a possible interaction between bupropion and a serotonergic drug was thought to have led to serotonin syndrome. The review also identified 6 cases with good evidence of an association with an overdose of bupropion. In the majority of these cases the patients had intentionally taken more than the prescribed dose.
The product information (summary of product characteristics and patient information leaflet) has been updated to include post-marketing reports of serotonin syndrome when bupropion is co-administered with a serotonergic agent such as selective serotonin reuptake inhibitors (SSRI) or serotonin norepinephrine re-uptake inhibitors (SNRIs). If concomitant treatment with other serotonergic agents is clinically warranted, the patient should be advised of the milder symptoms of serotonin syndrome and told to seek advice should they occur, particularly during treatment initiation and dose increases. Advice that serotonin syndrome has been reported in cases of overdose also been included in the product information.
In the UK up to October 2020, the Yellow Card scheme has received 3 reports of serotonin syndrome associated with bupropion, one of which was a potential overdose of bupropion and two of which were associated with concomitant use of antidepressant medicines.
Serotonin syndrome – signs and symptoms
Serotonin syndrome is an iatrogenic disorder of serotonergic hyperstimulation in which the underlying mechanism is thought to involve excessive stimulation of 5-HT1A receptors. It occurs most commonly when two or more serotonergic agents with different pharmacological mechanisms are administered either concurrently or sequentially without a sufficient washout period. However, it can also be associated with a single serotonergic agent, particularly at a high dose.
Signs and symptoms of serotonin syndrome may include mental-status changes (for example, agitation, hallucinations, coma), autonomic instability (for example, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (for example, hyperreflexia, incoordination, rigidity), and gastrointestinal symptoms (for example, nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, a dose reduction or discontinuation of bupropion therapy should be considered, depending on the severity of the symptoms.
Advice for patients
Ensure at initiation of bupropion that patients are aware that they should return for a review of their medication, especially if they are also taking medicines for depression (such as SSRI or SNRI), if they experience any of the following side effects:
- mental status changes (for example, agitation, hallucinations),
- gastrointestinal symptoms (for example, nausea, vomiting, diarrhoea
- body temperature above 38°C
- increase in heart rate
- signs of unstable blood pressure such as facial flushing, headaches, sweating, short periods of dizziness
- exaggeration of reflexes
- muscular rigidity
- lack of coordination
Early symptoms may be gastrointestinal symptoms or increased heart rate and agitation.
About bupropion signalling pathways
Bupropion is a norepinephrine–dopamine reuptake inhibitor (NDRI). Although bupropion mainly has an effect on dopamine and noradrenaline reuptake, there is some published evidence to suggest cross-reactivity between dopaminergic, noradrenergic, and serotonergic signalling in the central nervous system.[footnote 1][footnote 2] The exact relationship between these signalling pathways remains unclear.
Report to the Yellow Card scheme
Please report medication errors resulting in harm, including overdose and accidental exposure to a medicine, or any other suspected side effects on a Yellow Card.
Your report helps to improve the safety of medicines in the UK. Never assume someone else will report an adverse drug reaction – if in doubt, report.
Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:
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the Yellow Card app; download from the Apple App Store or Google Play Store
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some clinical IT systems for healthcare professionals (EMIS, SystmOne, Vision, MiDatabank, and Ulysses)
When reporting please provide as much information as possible, including information about medical history, any concomitant medication, onset, treatment dates, and product brand name.
Article citation: Drug Safety Update volume 14, issue 4: November 2020: 4.
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Cooper BR and others. ‘Behavioral and biochemical effects of the antidepressant bupropion (Wellbutrin): evidence for selective blockade of dopamine uptake in vivo’. Journal of Pharmacology and Experimental Therapeutics 1980; volume 215: pages 127–134. ↩
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Warner C, Shoaib M. ‘How does bupropion work as a smoking cessation aid?’ Addict Biol 2005; volume 10: pages 219–31. ↩
Updates to this page
Last updated 16 November 2020 + show all updates
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Added to DSU November
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First published.