How does Bupropion (Wellbutrin) work?

From the Guidelines

Wellbutrin (bupropion) works by inhibiting the reuptake of dopamine and norepinephrine in the brain, which increases the levels of these neurotransmitters in the synaptic cleft. This mechanism makes it effective for treating depression and as an aid for smoking cessation.

Key Points

• Unlike many other antidepressants, it has minimal effect on serotonin.
• Wellbutrin typically takes 2-4 weeks to reach full therapeutic effect, with dosages ranging from 150-450 mg daily depending on the formulation (immediate-release, sustained-release, or extended-release) 1.
• The medication is usually started at a lower dose (150 mg daily) and gradually increased to minimize side effects like insomnia, dry mouth, headache, and agitation.
• Wellbutrin is unique among antidepressants as it's less likely to cause sexual dysfunction or weight gain, making it a good option for patients concerned about these side effects, as noted in studies comparing its adverse event profile to other antidepressants like fluoxetine or sertraline 1.
• It should not be used by people with seizure disorders, eating disorders, or those abruptly discontinuing alcohol or sedatives due to an increased seizure risk.

Important Considerations

• Clinicians should assess patient status, therapeutic response, and adverse effects of antidepressant therapy on a regular basis beginning within 1 to 2 weeks of initiation of therapy, as recommended by the American College of Physicians 1.
• Patients should be monitored for the emergence of agitation, irritability, or unusual changes in behavior, because these symptoms can indicate that the depression is getting worse.
• The risk for suicide attempts is greater during the first 1 to 2 months of treatment, and thus close monitoring is advised by the U.S. Food and Drug Administration 1.

From the FDA Drug Label

The mechanism of action of bupropion is unknown, as is the case with other antidepressants. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine and does not inhibit monoamine oxidase or the reuptake of serotonin.

Bupropion's exact mechanism of action is unknown. However, it is thought to be related to its effects on noradrenergic and/or dopaminergic mechanisms. The drug is a weak inhibitor of norepinephrine and dopamine reuptake, but it does not affect serotonin reuptake or monoamine oxidase activity. 2

From the Research

Mechanism of Action

• Bupropion is presumed to be a dopamine-norepinephrine reuptake inhibitor 3, 4, 5, 6
• The mechanism of action of bupropion is still uncertain but may be related to inhibition of presynaptic dopamine and norepinephrine reuptake transporters 5
• Bupropion may also increase the activity of vesicular monoamine transporter-2, the transporter pumping dopamine, norepinephrine, and serotonin from the cytosol into presynaptic vesicles 5

Pharmacokinetics

• Bupropion is extensively metabolized by the liver with a half-life of approximately 21 hours 7
• The primary active metabolite of bupropion is hydroxybupropion, which is formed by cytochrome P450 2B6 7
• Bupropion has two other active metabolites, threohydrobupropion and erythrohydrobupropion, which are formed via nonmicrosomal pathways 7

Formulations

• Bupropion is available in three oral formulations: immediate release (IR), sustained release (SR), and extended release (XL) 3, 4, 7
• The three formulations are bioequivalent in terms of systemic exposure to bupropion 3, 4, 7
• The XL formulation has a prolonged absorption compared to the IR and SR formulations 7