Bupropion (Wellbutrin) as an alternative medication for SSRI intolerance

Ruslan Dorfman, PhD, MBA4 Apr 2025

Bupropion (Wellbutrin) is a “second generation” antidepressant that differs from SSRIs. Bupropion acts as a norepinephrine–dopamine reuptake inhibitor and has a much lower involvement of the serotonin pathway. Therefore, bupropion is frequently used for people who did not respond to or could not tolerate SSRIs. In addition to depression treatment, bupropion is also used to aid smoking cessation, ADHD and other conditions. However, bupropion does not work for everyone. Here we explain why bupropion can be a better choice for some and how to know if it may work for you.

SSRIs vs bupropion

Both SSRIs and bupropion are used to treat depression, anxiety, seasonal affective disorders, and adjunctive for addiction treatment. However, compared to SSRIs, bupropion was less effective in clinical trials for panic disorder, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD).

Bupropion does not decrease libido and could be a better choice for those who experience SSRI-induced sexual dysfunction. In addition, bupropion is more likely to induce weight loss; thus, it could be preferable for people that gain unwanted weight gain with SSRIs. In combination, bupropion with naltrexone (Contrave) is prescribed for treatment of obesity. The most common side effects of bupropion are constipation, dry mouth, and nausea, which often improve after 1-2 weeks of continuing the medication.

Comparison of the side effects of bupropion vs. a common SSRI

Different enzymes metabolize SSRIs and bupropion

Liver enzymes are responsible for the metabolism of most antidepressants. Each person has a unique genetic profile that can affect drug levels in the blood, thus impacting medication effectiveness and the risk of side effects.

Medication(s)	Liver Enzyme
bupropion	activated by CYP2B6
(es)citalopram	eliminated by CYP2C19
duloxetine	eliminated by CYP2D6 and CYP1A2
fluoxetine, paroxetine	eliminated by CYP2D6
sertraline	eliminated by CYP2C19 and CYP2B6
venlafaxine	eliminated by CYP2C19 and activated by CYP2D6
vortioxetine	eliminated by CYP2D6 and CYP3A4

Genetic variations in CYP2B6, CYP2C19 and CYP2D6 are common – most people have altered function in at least one of these enzymes. A pharmacogenetic test can reveal your metabolizer status for each enzyme. Knowing your pharmacogenetic profile helps your doctor to select the antidepressant which is better suited to your DNA and avoid those likely to cause serious side effects.

Because bupropion metabolism does not involve the CYP2D6 and CYP2C19 enzymes that impact most antidepressants, it may work better for people who are Poor or/and Ultrarapid metabolizers for these enzymes. However, bupropion requires another enzyme called CYP2B6 for its conversion to a more active form called hydroxybupropion. People who have reduced CYP2B6 activity may have reduced response to bupropion at standard doses. For Poor CYP2B6 metabolizers, bupropion may not work at all because of insufficient drug metabolism. In contrast, people that carry the *22 allele in the CYP2B6 have higher enzyme activity and may experience side effects at higher drug dose ranges.

Is bupropion safe to take with other medications?

It is important to know that bupropion is a strong inhibitor of the CYP2D6 enzyme, which metabolizes many antidepressants and antipsychotics. Therefore, it is not usually advisable to combine bupropion with fluoxetine, sertraline, haloperidol, risperidone, and metoprolol. Furthermore, bupropion can completely block potent opioid painkillers, including tramadol, oxycodone and codeine and reduce the effectiveness of these medications. If you are already taking bupropion and tramadol, oxycodone or codeine, it could be very dangerous stopping bupropion first. Please consult with your pharmacist or doctor before changing drug dose or stopping medications.

Which antidepressant is best for me?

Pharmacogenetic testing is now recognized as a valuable clinical tool to assist physicians in improving the management of anxiety, depression and other mental health conditions. If you cannot tolerate SSRIs or did not get a sufficient response from one or more antidepressants, consider getting a pharmacogenetic test such as Pillcheck. The Pillcheck report includes over 50 mental health drugs, including bupropion and many other antidepressants and antipsychotics. As part of the service, a Pillcheck pharmacist will review all your medications to reduce your risk of drug-drug and drug-gene interactions.