Bupropion – Mechanism of Action | Psychopharmacology | Clinical Application

MECHANISM OF ACTION OF BUPROPION

Bupropion and its three main metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion) have significant central noradrenergic activity at clinically relevant doses.

The mechanism of action is also uniquely different to other antidepressants. It enhances monoaminergic neurotransmission not through binding to pre-or post-synaptic serotonin receptors but by reducing the reuptake of dopamine and norepinephrine. [Ascher et al. 1995]

• Bupropion is classed as a dual norepinephrine and dopamine reuptake inhibitor (NDRI)
• Research shows that bupropion’s activity increases extracellular dopamine and norepinephrine concentrations in both the nucleus accumbens and the prefrontal cortex. [Nomikos et al 1989]; [Nomikos et al 1992]
• It has no affinity for post-synaptic histamine, α- or β-adrenergic, serotonin, dopamine, or acetylcholine receptors, differentiating it from most other antidepressants.

PHARMACOKINETICS AND INTERACTIONS OF BUPROPION

Pharmacokinetics

• Bupropion has an elimination half-life of 21 hours, and steady-state is generally reached within 8 days. [Wellbutrin PI]
• Peak plasma concentrations of hydroxybupropion are approximately 7 times the peak level of the parent drug at a steady state.
• Although bupropion reaches peak plasma concentrations within 2 hours, it is extensively metabolised, with only 5 to 20% reaching the systemic circulation.
• Bupropion’s metabolites are pharmacologically active; however, hydroxybupropion is half as potent, whereas threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion.

Drug interactions

Bupropion is extensively metabolised and therefore has a high potential for drug-drug interactions. Hydroxybupropion is formed after bupropion is metabolised by CYP2B6 [Faucette et al. 2000] whereas threohydrobupropion and erythrohydrobupropion are formed after carbonyl reduction by 11β-hydroxysteroid dehydrogenase (11β-HSD). [Wang et al. 2011]

• The antiretroviral drug ritonavir is a potent inducer of CYP2B6, and studies show that 100 mg and 600 mg can reduce the peak serum concentrations of bupropion by 21% and 62%, respectively. [Park et al. 2010]
• In addition, the antiretroviral efavirenz is another CYP2B6 inducer, and studies show that 600 mg reduces the peak serum concentrations of bupropion by 34%.  [Robertson et al. 2008]

CYP2D6

Furthermore, bupropion and hydroxybupropion are inhibitors of CYP2D6. Therefore, drugs metabolized by this isoenzyme should be used with caution, i.e., they should be administered at the lower end of the dose range.

This includes tricyclic antidepressants (nortriptyline, imipramine, and desipramine), SSRIs (Fluoxetine, Paroxetine, and Sertraline), and antipsychotics (haloperidol, risperidone, and thioridazine).

DOSING OF BUPROPION

• Bupropion is available in 75 mg and 100 mg tablets.
• Bupropion SR (Sustained Release) is available as 100 mg, 150 mg and 200 mg. Zyban (Bupropion SR) in Australia is available as 150 mg tablets.
• Bupropion XL (Extended-release) is available as 150 mg, 300 mg and 450 mg.
• Bupropion Hydrobromide is available as 174 mg, 378 mg and 522 mg.

Immediate release is best dosed three times a day; SR twice a day and XL once a day.

Depression: 

Bupropion immediate release 

• Start at 75 mg BD
• Increase to 100 mg BD
• Increase to 100 mg TDS
• Maximum dose 450 mg OD

Bupropion SR:

• 100 mg BD
• Increase to 150 mg BD after 3 days
• Wait 4 weeks or longer before further increases
• Maximum dose 400 mg /day

Bupropion XL:

• 150 mg XL OD
• Increase to 300 mg OD after 4 days
• Maximum dose 450 mg /day

For smoking cessation:

• Start treatment while the patient is still smoking and set a “target stop date” within the first two weeks of treatment with Bupropion SR (ZYBAN SR), preferably in the second week.
• Start with 150 mg OD for three days
• Increase to 150 mg BD.
• There should be an interval of at least 8 hours between successive doses.
• The maximum single dose must not exceed 150 mg, and the maximum total daily dose must not exceed 300 mg.
• Continue for at least 7 weeks. Treatment up to 1 year is effective.

SIDE EFFECTS

The most common side effect of bupropion treatment is agitation, which is also the primary reason for discontinuation.

Other common adverse effects in RCTs (≥15%) include dry mouth, constipation, headache, dizziness, excessive sweating, nausea, tremor, sedation, and insomnia. [Settle et al. 1999]

Bupropion also comes with a boxed warning for serious neuropsychiatric symptoms and suicide risk in those who are using bupropion for smoking cessation. This includes changes in mood, psychosis, hallucinations, paranoia, delusions, homicidal ideation, and suicidal ideation. These symptoms have been reported in patients with and without a pre-existing psychiatric disease.

Patients with hepatic and renal impairment have a greater risk of adverse effects due to drug and metabolite accumulation and should consider a reduced frequency and/or dose reduction. Finally, bupropion also comes with several other precautions:

• Clinicians should consider altered appetite observed in 28% of patients with >2kg weight loss and the anorectic potential.
• Hypersensitivity and anaphylactoid/anaphylactic reactions (skin rash, hives, chest pain, oedema, and shortness of breath) have been reported in post-marketing studies.
• Some patients have also reported cardiovascular effects such as treatment-emergent hypertension, even in patients with no pre-existing hypertension.

CLINICAL EVIDENCE

Depression:

• Bupropion is an efficacious antidepressant. [Patel et al., 2016]
• The evidence is in favour of bupropion producing no weight gain (typically weight loss) and that it can improve sexual functioning in depressed individuals. [See interview with Prof Clayton on Sexual Side Effects of Antidepressants]
• Hypersomnia, Hyperphagia and fatigue are clinical characteristics in depression for which Bupropion may be chosen.
• The RANZCP 2020 mood disorder guidelines mention Bupropion as a choice antidepressant for depression when the clinical feature of fatigue is present. It may thus be useful in chronic fatigue syndrome.

Bipolar Depression:

• Bupropion is an efficacious antidepressant in treating depressive episodes in Bipolar disorder similar to those of other antidepressants.
• SSRIs and bupropion should, in general, be prescribed for bipolar patients before SNRIs due to higher switch rates associated with the latter—but some bipolar patients will need to be treated with an SNRI. [Gitlin, 2018]
• However, the rate of phase-shifting (manic switch) with bupropion usage was not as low compared to other antidepressants as previously thought. Thus clinicians should be aware of the risk of phase-shifting when prescribing bupropion to BD patients regardless of the suggestions of current clinical practice guidelines. [Li et al., 2016]

Smoking cessation:

• Bupropion is effective in smoking cessation and can be combined with NRT and varenicline. Bupropion is less effective than varenicline. [Howes et al., 2020]
• Combination varenicline/bupropion treatment proved significantly more efficacious than varenicline alone for male smokers or smokers with a high degree of dependence who did not show a sufficient initial response to pre-quit nicotine patch treatment. [Rose & Behm, 2014]

ADHD

• Bupropion may lead to a small improvement in ADHD, and it may also decrease symptoms related to ADHD. The drug does not have more adverse effects than treatment with placebo. Bupropion may be an alternative treatment for adults with ADHD who cannot or will not take stimulant drugs. [Verbeeck et al., 2017]

Obesity:

• While not routine, the Naltrexone/Bupropion combination is evidence-based in the treatment of antipsychotic weight gain. [Greig & Keating, 2015] [Read more about managing obesity and weight gain in psychiatry]
• Studies have shown the combination is associated with a decrease in body weight by 3.2-5.2% compared with placebo. In comparison, approximately half of treated patients experience a greater than 5% decrease in body weight. In diabetic patients, a decrease of glycated haemoglobin by approximately 0.5% was also noticed. The most common adverse effects of the drug include nausea, vomiting and headache. Thus it may also be useful in obese patients with an alcohol use disorder.

Methamphetamine Use Disorder

A study published in the New England Journal of Medicine in January 2021 reported the results of a multisite RCT investigating the use of oral extended-release (XL) bupropion (450 mg/day) and injectable naltrexone (380 mg every 3 weeks) for methamphetamine use disorder. [Trivedi et al. 2021]

Formulations used were an oral extended-release bupropion and extended-release injectable naltrexone.

• At weeks 5 and 6, 16.5% of patients administered the combination therapy responded, compared to only 3.4% in the placebo group.
• At weeks 11 and 12, 11.8% of patients administered the combination therapy responded, compared to only 1.8% in the placebo group.
• The number needed to treat (NNT), used to calculate how many patients would need to receive treatment for it to benefit one person, was 9.
• The treatment effect was statistically significant (P<0.001).

SUMMARY

Bupropion is an antidepressant with a unique but not fully understood mechanism of action as a norepinephrine–dopamine reuptake inhibitor.

It is frequently prescribed for depression, seasonal affective disorder, and smoking cessation and has several advantages over other antidepressants, particularly where weight gain or sexual dysfunction are significant problems.