Does Wellbutrin and Zoloft work well together? (+9 effects)

In this article, we will discuss whether Wellbutrin and Zoloft work well together. We will also state the benefits of combining these two medications and what are the possible side effects that can result from this combination.


Does Wellbutrin and Zoloft work well together? 

Yes, Wellbutrin and Zoloft can work well together. Wellbutrin and Zoloft are both classified as antidepressant medications, yet their mechanisms of action differ. Wellbutrin predominantly influences the neurotransmitters dopamine and norepinephrine. Whereas Zoloft, as a selective serotonin reuptake inhibitor (SSRI), primarily targets serotonin levels in the brain. 

In some cases, healthcare professionals may prescribe Wellbutrin and Zoloft in combination. This combination can be beneficial in certain situations such as failed monotherapy treatment(1). However, it’s important to note that this combination can be beneficial for some individuals but not for everyone.

Your healthcare provider must evaluate your symptoms, medical history and your responses to previous medications and then decide whether to give you the combination therapy or not.

What are the benefits of combining Zoloft and Wellbutrin?

Combining Zoloft (sertraline) and Wellbutrin (bupropion) can present various potential advantages, particularly for individuals dealing with certain forms of depression. Here are some of the benefits of combining these medications:

  • Improved efficacy: Using a combination of two antidepressants that act on distinct neurotransmitters (serotonin and dopamine/norepinephrine) offers a more comprehensive approach to treating depression. (2)


  • Targeting different symptoms: Zoloft manages symptoms such as low mood, excessive worry and anxiety. While Wellbutrin targets other symptoms such as lack of motivation and impaired concentration and focus.


  • Treating resistant depression: Sometimes depressive symptoms are not treated adequately with a single medication; therefore, combining Zoloft and Wellbutrin with their different mechanisms of action might improve the chances of treating depressive symptoms.


  • Quitting smoking: Wellbutrin can also be used as a smoking cessation aid. Combining it with Zoloft can help manage both depression and the challenges associated with quitting smoking. (3)


What does the research suggest? 

A clinical trial was conducted on a group of depressed patients who had persistent depressive symptoms despite taking the appropriate treatment. A combination treatment of Zoloft and Wellbutrin was then introduced to address persistent major depression in patients. This approach proved to be highly effective in treating depressive symptoms, with no reported adverse effects among the patients.

The effective combination of Zoloft and Wellbutrin is because of the synergistic interaction that produced an effect greater than the sum of their individual effects. This is due to the combination effect of two different antidepressants that work on all serotonergic, noradrenergic and dopaminergic systems. (2)

Potential adverse effects of taking Zoloft and Wellbutrin together?

The combination of Zoloft and Wellbutrin can yield both therapeutic effects and potential adverse effects. When these two medications are prescribed together, it’s important to be aware of the following adverse effects that can occur:

Serotonin syndrome: It’s a life-threatening condition that occurs due to excessive serotonin levels in the brain and causes symptoms such as agitation, hallucinations, rapid heart rate, muscle spasms, tremors, stomach cramps, nausea, vomiting and diarrhea. Serotonin syndrome requires immediate medical attention.(3)

Seizures: Both Zoloft and Wellbutrin can increase the risk of seizures especially when given at higher doses.(5)

Insomnia: Both Zoloft and Wellbutrin can interfere with sleep patterns. Combining them can exacerbate sleep disturbances.(3)

Gastrointestinal problems: Taking Zoloft and Wellbutrin together can exacerbate gastrointestinal issues such as nausea, vomiting, diarrhea or stomach cramps. (4)

Weight changes: Zoloft is associated with weight gain in some individuals, while Wellbutrin is considered weight-neutral or may even cause weight loss. However, Wellbutrin can cause bloating. Combining both medications might result in varying effects on body weight.(1)



Wellbutrin and Zoloft work well together. Combining them has a better therapeutic effect, but it may increase the risk of side effects associated with both medications. It’s crucial to use these medications under the close supervision of a healthcare provider who can monitor for adverse effects and adjust the dosages or treatment plan as needed.

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Ravindran PP, Zang W, Renukunta S, Mansour R, Denduluri S. Effect of comedication of bupropion and other antidepressants on body mass index. Ther Adv Psychopharmacol. 2015Jun;5(3):15865


Marshall RD, Johannet CM, Collins PY, Smith H, Kahn DA, Douglas CJ. Bupropion and sertraline combination treatment in refractory depression. Journal of Psychopharmacology. 1995;9(3):284-286.


Moret C. Combination/augmentation strategies for improving the treatment of depression. Neuropsychiatr Dis Treat. 2005 Dec;1(4):301-9.


Wang Z, Li H, Kang Y, Liu Y, Shan L, Wang F. Risks of Digestive System Side-Effects of Selective Serotonin Reuptake Inhibitors in Patients with Depression: A Network Meta-Analysis. Ther Clin Risk Manag. 2022 Aug 13;18:799-812. doi:10.2147/TCRM.S363404


Hill T, Coupland C, Morriss R, Arthur A, Moore M, Hippisley-Cox J. Antidepressant use and risk of epilepsy and seizures in people aged 20 to 64 years: cohort study using a primary care database. BMC Psychiatry. 2015 Dec 17;15:315.

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