Mechanism of Action of Wellbutrin (Bupropion)
Bupropion works primarily by inhibiting the reuptake of norepinephrine and dopamine neurotransmitters, without significant effects on serotonin neurotransmission. 1, 2
Primary Neurochemical Effects
- Bupropion is a relatively weak inhibitor of neuronal uptake of norepinephrine and dopamine 1
- Unlike many other antidepressants, bupropion does not inhibit monoamine oxidase or affect serotonin reuptake 1, 2
- The medication activates the central nervous system to release norepinephrine, dopamine, and other neurotransmitters 3
- Bupropion's mechanism differs from traditional antidepressants like SSRIs, which primarily affect serotonin 2, 4
Metabolic Considerations
- Bupropion undergoes extensive metabolism in humans to form three active metabolites: hydroxybupropion, threohydrobupropion, and erythrohydrobupropion 1
- Hydroxybupropion is formed via hydroxylation of the tert-butyl group of bupropion, primarily through the CYP2B6 enzyme 1
- The amino-alcohol isomers threohydrobupropion and erythrohydrobupropion are formed via reduction of the carbonyl group 1
- The metabolites, particularly hydroxybupropion, contribute to the clinical effects of bupropion as they reach plasma concentrations as high or higher than the parent drug 1, 2
Hypothalamic Effects
- Bupropion administration leads to increased activation of anorexigenic neurons in the hypothalamus 3
- This hypothalamic effect helps explain why bupropion is considered weight-neutral or weight-loss promoting, unlike many other antidepressants that cause weight gain 5, 6
- Clinical trials have found that bupropion decreases body weight by suppressing appetite and reducing food cravings 5
Clinical Implications of Mechanism
- The unique dual norepinephrine and dopamine reuptake inhibition mechanism explains bupropion's distinctive clinical profile 4
- Unlike serotonergic antidepressants, bupropion has a lower incidence of sexual dysfunction, weight gain, and somnolence 7, 4
- Common side effects related to its mechanism include nervousness and insomnia, reflecting its activating properties 2
- Extended-release formulations moderate the stimulant-like effects by providing gradual drug delivery 6
- The mechanism also explains bupropion's efficacy in smoking cessation, as dopaminergic effects may help reduce nicotine cravings 2, 8
Important Distinctions from Other Antidepressants
- Bupropion is chemically unrelated to tricyclic, tetracyclic, or selective serotonin reuptake inhibitor antidepressants 1
- Its structure closely resembles that of diethylpropion and is related to phenylethylamines 1
- The lack of serotonergic activity distinguishes bupropion from most other modern antidepressants 2, 4
- This unique pharmacological profile makes bupropion particularly useful for patients who experience side effects with serotonergic antidepressants 8, 4