Bupropion

Indications

• FDA-approved for major depressive disorder in adults in immediate-release, sustained-release, and extended-release formulations.
• FDA-approved as the extended-release tablet for prevention of seasonal affective disorder, started in autumn before symptoms typically begin.
• FDA-approved as Zyban for smoking cessation, begun one to two weeks before the target quit date and continued 7 to 12 weeks.
• Combined with dextromethorphan as Auvelity for major depressive disorder and with naltrexone as Contrave for chronic weight management.
• Off-label for adult ADHD, for antidepressant-induced sexual dysfunction as an add-on, and for augmenting a partially effective SSRI.
• Off-label for methamphetamine use disorder in combination with injectable naltrexone, supported by a randomized multisite trial.

Mechanism of action

• Inhibits the norepinephrine and dopamine transporters with essentially no effect on serotonin reuptake, which is unique among antidepressants.
• The absence of serotonergic action explains why it does not cause sexual dysfunction, weight gain, or serotonin syndrome.
• Its active metabolite hydroxybupropion contributes substantially to effect and reaches concentrations several times those of the parent drug.
• It is also a noncompetitive nicotinic acetylcholine receptor antagonist, which underlies its efficacy in smoking cessation.
• Dopaminergic and noradrenergic activation lowers the seizure threshold in a concentration-dependent manner, the defining safety limit.

Pharmacokinetics

• Rapidly absorbed with extensive first-pass metabolism; food has little effect, though the extended-release shell may appear intact in stool.
• Half-life is about 21 hours for bupropion and roughly 20 hours for the active metabolite hydroxybupropion.
• CYP2B6 generates hydroxybupropion, so CYP2B6 inducers and inhibitors shift the balance between parent drug and metabolite.
• Bupropion and hydroxybupropion are both potent CYP2D6 inhibitors, which is the drug's single most important interaction property.
• In severe cirrhosis both the parent and metabolite accumulate markedly, requiring dosing no more often than every other day.

Dosing

• Immediate-release starts at 100 mg twice daily, may go to 100 mg three times daily, with a 150 mg single-dose cap and 450 mg/day total.
• Sustained-release starts at 150 mg each morning, increases to 150 mg twice daily at least 8 hours apart, with a maximum of 400 mg/day.
• Extended-release starts at 150 mg each morning and increases to 300 mg each morning after four days, with a maximum of 450 mg/day.
• Aplenzin uses the hydrobromide salt, where 174, 348, and 522 mg correspond to 150, 300, and 450 mg of bupropion hydrochloride.
• In severe hepatic impairment give no more than 150 mg every other day; reduce the dose or frequency in renal impairment as well.
• Give the last dose before mid-afternoon to limit insomnia, and taper is generally unnecessary given the absence of a withdrawal syndrome.

Adverse effects

• Insomnia, dry mouth, headache, nausea, tremor, agitation, and anxiety are the most common effects and reflect its activating profile.
• Seizure incidence is about 0.1 percent at 300 mg/day of the sustained-release form and rises to roughly 0.4 percent at 450 mg/day.
• Weight loss occurs in about 25 percent of patients, and it is essentially free of the sexual dysfunction that limits SSRIs and SNRIs.
• Hypertension can worsen, particularly when combined with nicotine replacement, so blood pressure should be checked during titration.
• Psychosis, mania, and severe agitation can be precipitated, and the risk is highest in undiagnosed bipolar disorder.
• Bupropion causes false-positive amphetamine results on urine immunoassay screening, which requires confirmatory testing.

Monitoring

• Screen at baseline for seizure history, head injury, eating disorder, and any plan to stop alcohol or benzodiazepines abruptly.
• Check blood pressure at baseline and during titration, especially when a nicotine patch or a stimulant is used concurrently.
• Assess suicidality, activation, agitation, and sleep weekly for the first four weeks and after each dose increase.
• Review the medication list for CYP2D6 substrates at initiation and whenever a new drug is added, since inhibition is potent.
• Track response with the PHQ-9 every two to four weeks and reassess the diagnosis if activation increases without mood improvement.

Interactions

• Contraindicated in seizure disorder, in current or prior bulimia or anorexia nervosa, and with abrupt cessation of alcohol or sedatives.
• Contraindicated with MAOIs and within 14 days of stopping one, and with linezolid or intravenous methylene blue.
• Potent CYP2D6 inhibition raises levels of tricyclics, metoprolol, atomoxetine, risperidone, and vortioxetine and blocks tamoxifen activation.
• Additive seizure risk with tramadol, theophylline, systemic steroids, antipsychotics, and stimulants, and with any condition lowering the threshold.
• CYP2B6 inducers such as ritonavir, efavirenz, and carbamazepine substantially reduce bupropion levels and may cause apparent nonresponse.

Special populations

• Pregnancy data are reasonably reassuring overall, and bupropion is often continued when it is the only agent that has worked.
• Relative infant dose in breast milk is low, but rare infant seizures have been reported, so monitor the infant if breastfeeding.
• Not approved in pediatrics for depression; adult ADHD data are stronger than pediatric ADHD data, and both uses are off-label.
• In older adults reduce the dose and watch for agitation, insomnia, and hyponatremia, though hyponatremia is rarer than with SSRIs.
• In severe hepatic impairment cap at 150 mg every other day; in renal impairment reduce dose or frequency because metabolites accumulate.

Clinical pearls

• The antidepressant that does not cause sexual dysfunction or weight gain, which drives most of its use.
• Absolutely contraindicated in seizure disorder and in any history of bulimia or anorexia nervosa.
• Potent 2D6 inhibitor: recheck metoprolol, atomoxetine, and tamoxifen whenever you add it.