What is Bupropion (Extended Release/Sustained Release)?

What is Bupropion ER/SR?

Bupropion Extended Release (ER) and Sustained Release (SR) are modified-release formulations of an aminoketone antidepressant that works primarily by inhibiting dopamine and norepinephrine reuptake, with additional effects as a nicotinic acetylcholine receptor antagonist. 1, 2

Chemical Structure and Formulations

• Bupropion hydrochloride is chemically unrelated to tricyclic, tetracyclic, or SSRI antidepressants, with a structure resembling diethylpropion and phenylethylamines (molecular formula: C13H18ClNO•HCl, molecular weight: 276.21 g/mol) 1

• Three distinct oral formulations exist with different dosing schedules but bioequivalent systemic exposure: 3

  • Immediate Release (IR): administered three times daily 3
  • Sustained Release (SR): administered twice daily, typically 150 mg twice daily for a total of 300 mg/day 4, 3
  • Extended Release (XL/XR): administered once daily, typically 300 mg in the morning 4, 3

FDA-Approved Indications

• Major Depressive Disorder (MDD) is the primary FDA-approved indication for bupropion 5

• Smoking cessation is approved under the brand name ZYBAN (same active ingredient as bupropion) 1

Mechanism of Action

• Bupropion acts through multiple pathways: inhibition of dopamine reuptake, weak norepinephrine reuptake inhibition, and antagonism of nicotinic acetylcholine receptors 2, 6

• Unlike SSRIs, bupropion has no effect on the serotonin system 6

Standard Dosing Regimens

For Major Depressive Disorder:

• Bupropion SR: Start with 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) 4
• Maximum dose: 400 mg per day for SR formulation, 450 mg per day for XL formulation 4

For Smoking Cessation:

• Standard dosing: 150 mg twice daily (300 mg total) of the SR formulation 2, 4
• Treatment should begin 1-2 weeks before the target quit date to establish therapeutic drug levels before cessation attempts 4
• Typical treatment duration: 7-12 weeks, with efficacy assessed after this period 2, 4

Critical Safety Considerations

Seizure Risk:

• Bupropion lowers the seizure threshold with a dose-related risk of approximately 0.1% at doses up to 450 mg/day, increasing nearly 10-fold between 450-600 mg/day 2, 1

• Absolute contraindications include: seizure disorders, current or prior anorexia nervosa or bulimia, abrupt discontinuation of alcohol/benzodiazepines/barbiturates/antiepileptic drugs 1

• Additional risk factors include severe head injury, CNS tumors, severe stroke, metabolic disorders (hypoglycemia, hyponatremia, severe hepatic impairment), and concomitant medications that lower seizure threshold 1

Neuropsychiatric Effects:

• While neuropsychiatric adverse events (depression, mania, psychosis, hallucinations, suicidal ideation) have been reported, the EAGLES trial (n=8,144) found no significant increase in neuropsychiatric events with bupropion compared to nicotine patch or placebo 2

• Serious neuropsychiatric adverse events are rarely associated with bupropion prescribed for smoking cessation, even in patients with mental illness 2

Cardiovascular Concerns:

• Bupropion can cause elevated blood pressure and hypertension, requiring blood pressure monitoring before and during treatment 1

• The combination of bupropion SR with nicotine transdermal system (NTS) showed higher treatment-emergent hypertension (6.1%) compared to bupropion alone (2.5%) 1

• Recent meta-analyses do not show elevated risk of serious adverse cardiovascular effects from bupropion use for smoking cessation 2

Special Population Dosing

Hepatic Impairment:

• For moderate to severe hepatic impairment, the total daily dose should not exceed 150 mg daily due to reduced drug clearance 4

Renal Impairment:

• For moderate to severe renal impairment (GFR <90 mL/min), reduce the total daily dose by half as bupropion and its metabolites are cleared renally and may accumulate 4

Older Adults:

• Start with 37.5 mg every morning, then gradually increase by 37.5 mg every 3 days as tolerated to minimize adverse reactions 4
• Maximum dose for older adults: 150 mg twice daily (300 mg total) 4
• Administer the second dose before 3 p.m. to minimize insomnia risk 4

Clinical Efficacy

For Smoking Cessation:

• A 2014 Cochrane review of 44 trials demonstrated a relative risk of 1.62 (95% CI, 1.49-1.76) for smoking cessation with bupropion 2

• The EAGLES trial showed bupropion achieved superior abstinence rates compared with placebo (OR, 2.07; 95% CI, 1.75-2.45), with efficacy similar to nicotine patch but less than varenicline 2

• Bupropion may be particularly beneficial for patients with comorbid depression who want to quit smoking, addressing both conditions simultaneously 2, 4

For Major Depressive Disorder:

• Bupropion SR demonstrated efficacy comparable to SSRIs but with advantages of less somnolence and sexual dysfunction 3

• Bupropion was as efficacious as tricyclic antidepressants with less somnolence and weight gain 3

Important Drug Interactions and Contraindications

• Contraindicated with MAOIs or within 14 days of discontinuing MAOIs due to increased risk of hypertensive reactions 4, 1

• Contraindicated in patients taking tamoxifen as bupropion may interfere with tamoxifen metabolism 4

• Bupropion is a potent enzyme inhibitor that can raise plasma levels of antidepressants, antiarrhythmics, and antipsychotics 6

• Patients should not combine bupropion formulations (e.g., taking both Wellbutrin and Zyban simultaneously) as they contain the same active ingredient 1

Administration Pearls

• Doses should be separated by at least 6 hours to minimize seizure risk 1

• Tablets must be swallowed whole and not crushed, divided, or chewed to maintain the extended/sustained release properties 1

• Can be taken with or without food 1

• If a dose is missed, do not double the next dose due to dose-related seizure risk 1