What is the mechanism of action of Wellbutrin (bupropion)?

Mechanism of Action of Wellbutrin (Bupropion)

Bupropion works primarily as a weak inhibitor of neuronal uptake of norepinephrine and dopamine, without significant effects on serotonin reuptake, making it unique among antidepressants. 1

Primary Mechanisms

• Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, which is presumed to mediate its therapeutic effects 1
• Unlike most antidepressants, bupropion does not inhibit monoamine oxidase or the reuptake of serotonin 1
• The medication is chemically unrelated to tricyclic, tetracyclic, or selective serotonin reuptake inhibitor antidepressants 1

Neurochemical Effects

• Bupropion administration leads to increased activation of anorexigenic neurons in the hypothalamus 2
• Sustained administration causes a significant increase in serotonin (5-HT) neuronal firing rate in the dorsal raphe nucleus, despite not directly affecting serotonin reuptake 3
• Initially attenuates norepinephrine neuronal firing in the locus coeruleus, which gradually recovers with continued administration 3
• Does not significantly alter dopamine neuronal firing in the ventral tegmental area with sustained administration 3

Receptor Interactions

• Bupropion causes desensitization of 5-HT1A autoreceptors after just two days of administration 3
• With prolonged administration (14 days), it leads to desensitization of alpha2-adrenoceptors 3
• The medication activates the central nervous system to release norepinephrine, dopamine, and other neurotransmitters 2

Metabolites and Pharmacokinetics

• Bupropion is extensively metabolized to three active metabolites: hydroxybupropion, threohydrobupropion, and erythrohydrobupropion 1
• Hydroxybupropion is formed via hydroxylation of the tert-butyl group primarily through the CYP2B6 enzyme 1
• Threohydrobupropion and erythrohydrobupropion are formed via reduction of the carbonyl group 1
• These metabolites reach plasma concentrations as high or higher than bupropion itself and contribute to its clinical effects 1
• Hydroxybupropion is approximately half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are about 5-fold less potent 1

Clinical Implications of Mechanism

• The unique mechanism of action makes bupropion effective for both depression and smoking cessation 4
• For smoking cessation, bupropion may attenuate withdrawal symptoms by mimicking nicotinic effects on dopamine and noradrenaline 5
• Its ability to antagonize nicotinic receptors may prevent relapse by reducing the reinforcing properties of nicotine 5
• Unlike many other antidepressants, bupropion is considered weight-neutral or weight-loss promoting due to its effects on hypothalamic neurons 6

Distinguishing Features

• Bupropion is the only antidepressant available in the United States with no appreciable activity on serotonin concentrations in the central nervous system 7
• Extended-release formulations provide gradual drug delivery, which moderates any stimulant-like effects 6
• The medication's structure closely resembles diethylpropion and is related to phenylethylamines 1

Bupropion's unique mechanism as a dual norepinephrine and dopamine reuptake inhibitor without significant serotonergic effects distinguishes it from other antidepressants and explains its efficacy in both depression treatment and smoking cessation.