Zoloft (sertraline) and Wellbutrin (bupropion) are effective, widely used antidepressants. They have different mechanisms of action, side effects, and uses, though, so it’s important to understand each before deciding which one might be right for you.
Deciding on any medication can be daunting. You need to take into consideration factors like your health, medical history, condition, symptoms, and lifestyle. In every case, it’s essential to talk to your doctor or a mental health provider to guide your decision.
Similarities Between Zoloft and Wellbutrin
There are several similarities between Wellbutrin compared to Zoloft, including their use for depression, their non-addictive nature, overlapping side effects, and how long they take to work.
Use for depression treatment
The FDA has approved both Wellbutrin and Zoloft for depression. Both medications can improve emotional and physical depressive symptoms, including persistent sadness, lack of interest, and difficulty concentrating. Research shows that many Zoloft and Wellbutrin users experience significant improvements in symptoms, even though the drugs belong to different classes and impact different brain chemicals.
Non-addictive nature
A major benefit of both antidepressants is that they’re not addictive. If you’re worried about dependency, Zoloft and Wellbutrin can be good options. They don’t cause cravings or severe withdrawal symptoms upon stopping, which differs from addictive substances. That said, if you’re considering discontinuing a medication, it’s always a good idea to talk to your doctor about a taper plan that allows you to gradually wean off your dosage to avoid withdrawal from Zoloft or Wellbutrin.
Overlapping side effects
Many drugs, including Zoloft and Wellbutrin, have overlapping side effects. For most people, the effects are mild and resolve over time as their body adjusts to having the medication in it.
Common Zoloft and Wellbutrin side effects can include:
- Insomnia
- Dry mouth
- Sweating
- Headache
- Dizziness
- Nausea
- Gastrointestinal issues like constipation
Sexual side effects like low libido or difficulty with orgasm are more common when taking Zoloft, but they can occasionally occur when taking Wellbutrin as well.
Delayed onset
Neither Zoloft nor Wellbutrin works immediately. It’s possible to start noticing an improvement in mood within a few weeks, but the full impact of these drugs typically isn’t felt for up to two months. You probably want to feel relief as soon as possible after you’re prescribed a new medication, it’s critical to be patient and give it time to work.
Differences Between Zoloft and Wellbutrin
No two drugs work the exact same way for everyone who uses them, and there are some distinct differences between Wellbutrin vs. Zoloft. Understanding how they differ means you know what to expect and when to expect it.
Medication type and how they work
The differences between two medications are often related to the class of drug they belong to and their mode of action.
Zoloft is a selective serotonin reuptake inhibitor (SSRI). SSRIs work by increasing serotonin levels in the brain. Serotonin is a neurotransmitter that’s associated with functions like mood regulation, appetite control, and sleep. It helps to stabilize mood and promotes feelings of happiness.
Wellbutrin belongs to a class of drugs called norepinephrine-dopamine reuptake inhibitors (NDRIs). They’re considered an “atypical antidepressant,” meaning they don’t work the same way as other antidepressants. NDRIs impact dopamine and norepinephrine instead of serotonin.
Dopamine and norepinephrine are neurotransmitters similar to serotonin, but they function in distinct ways. Dopamine affects mood, motivation, pleasure, and focus. Norepinephrine is linked to stress response, alertness, and attention, which helps with the fatigue and low energy that’s often part of depression.
Impact on energy, weight, and sleep
Wellbutrin is known for helping with energy levels and motivation, whereas Zoloft side effects might include fatigue and sleepiness, which isn’t ideal if your depression is already causing issues with alertness.
In terms of weight, modest weight gain from Zoloft is associated with long-term use, whereas Wellbutrin is more weight-neutral. In fact, some people even lose weight when taking Wellbutrin.
Risk factors
All medications, including Zoloft and Wellbutrin, have some level of risk. Both these drugs carry warnings about increased suicidal thoughts in younger people. There are also more severe side effects to be aware of, including seizures, which are rare but worth knowing about. Taking Zoloft and Wellbutrin together increases the risk of seizures and should only be done under close medical supervision.
“Zoloft can be a great option if a patient is struggling with symptoms of both anxiety and depression. However, caution should be used in prescribing Wellbutrin in the presence of significant anxiety as it can be too stimulating for some and thus can worsen the anxiety. With either medication, effectiveness will be assessed by the improvement in the original symptoms.”
- Talkspace psychiatric provider, Svetlana Stuck, PA-C
Suitability for anxiety vs. depression
If you experience anxiety linked to depression, Zoloft might be a better option because it directly enhances serotonin levels, which can help reduce anxiety. If your primary symptoms are low motivation, lack of energy, or difficulty concentrating, Wellbutrin may be a more suitable option.
FAQs About Zoloft vs. Wellbutrin
Is Zoloft better than Wellbutrin?
When comparing Zoloft vs. Wellbutrin, neither is “better.” The medication that works best for you depends on factors such as your symptoms, condition, medical history, side effect tolerability, and body chemistry. What works great for you might not work at all for someone else.
Which causes more weight gain?
Zoloft is associated with weight gain over time. However, it’s typically a modest increase. Results can vary from person to person, but Wellbutrin is generally considered weight-neutral, with some individuals even experiencing weight loss from Wellbutrin. It might be a preferred option to start with if you have concerns about weight gain.
Can you take Zoloft and Wellbutrin together?
Your doctor can prescribe Zoloft and Wellbutrin together in an effort to manage a broader range of symptoms. Because they target different brain chemicals, they might complement each other. However, combining them increases the risk of seizures, so it should be done only under close medical supervision. Only your doctor or a mental health provider can weigh the benefits and risks closely enough to help you make an informed decision.
“Zoloft and Wellbutrin can be used together to treat depression or comorbid conditions like depression and anxiety. In the presence of mainly depression symptoms, Wellbutrin may be effective by itself, especially if the symptoms are related to low mood, low motivation, trouble with focus, and low energy. Sometimes an SSRI like Zoloft may not be effective or may have side effects, so switching to Wellbutrin may be a good option to trial."
- Talkspace psychiatric provider, Svetlana Stuck, PA-C
Choosing Between Zoloft vs. Wellbutrin
Choosing the right medication to treat depression can feel overwhelming, but with your doctor’s help and by weighing all the factors, you can make a confident decision between Zoloft and Wellbutrin.
Doctor’s recommendations
A healthcare provider or mental health professional will gather information about your symptoms, medical history, and any comorbid conditions like anxiety or ADHD. They’ll also ask about your past experiences with medications and your daily lifestyle. It’s factors like these that help guide the decision between Zoloft vs. Wellbutrin.
Patient preferences and lifestyle
Your lifestyle and preferences are important to think about when selecting a drug. Your daily routine, concerns about side effects like weight gain or sexual dysfunction, and your energy levels will all be taken into consideration.
For example, if you’re worried about sexual dysfunction, Wellbutrin compared to Zoloft might have fewer side effects. If you struggle with fatigue, Wellbutrin has an activating effect that can be beneficial. On the other hand, if you have a history of panic attacks or obsessive-compulsive tendencies, Zoloft is FDA-approved to treat these conditions, while Wellbutrin isn’t.
Clinical considerations
Your doctor will closely consider your health history, any medications you’re taking now, and drugs you’ve taken in the past before deciding which antidepressant might be the safest and most effective.
Wellbutrin typically isn’t recommended if you’ve ever had an eating disorder or if you have a history of seizures. Zoloft can be a better option if you have bipolar disorder or any serotonin-related conditions. If you’re trying to quit smoking or struggle with fatigue, your doctor may suggest Wellbutrin, which is known to help with both.
“Typically, in the presence of multiple symptoms related to anxiety and depression, Zoloft may be a good option. However, in cases where Zoloft is not effective or there are side effects, a trial of Wellbutrin may be an option.”
- Talkspace psychiatric provider, Svetlana Stuck, PA-C
Get Professional Guidance with a Prescription
Choosing an antidepressant is a personal and complex process. Unfortunately, there’s no one-size-fits-all solution. By working with a psychiatrist or your primary care doctor, you can create a safe and effective treatment plan that fully addresses your needs.
If you’re not sold on either of these antidepressants, or you want to explore Zoloft and Wellbutrin alternatives to make an informed decision, connecting with an online psychiatric provider at Talkspace simplifies the process. They can offer personalized guidance, prescriptions, and follow-ups throughout your mental health journey. Reach out to explore a Zoloft or Wellbutrin prescription online today.
Sources:
- Pfizer Inc. Highlights of Prescribing Information for Zoloft.; 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019839s74s86s87_20990s35s44s45lbl.pdf. Accessed October 30, 2025.
- FDA. Prescribing Information for Wellbutrin (Bupropion Hydrochloride) Tablets. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018644s039s040.pdf. Accessed October 30, 2025.
- Valle-Cabrera R, Mendoza-Rodríguez Y, Robaina-García M, et al. Efficacy of sertraline in patients with major depressive disorder naive to selective serotonin reuptake inhibitors. Journal of Clinical Psychopharmacology. 2018;38(5):454-459. doi:10.1097/jcp.0000000000000950. https://pubmed.ncbi.nlm.nih.gov/30106883/. Accessed October 30, 2025.
- Fava M, Rush AJ, Thase ME, et al. 15 years of clinical experience with Bupropion HCL. The Primary Care Companion for CNS Disorders. 2005;7(3). doi:10.4088/pcc.v07n0305. https://pmc.ncbi.nlm.nih.gov/articles/PMC1163271/. Accessed October 30, 2025.
- Research C for DEA. Suicidality in children and adolescents being treated with antidepressant medications. U.S. Food And Drug Administration. February 5, 2018. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/suicidality-children-and-adolescents-being-treated-antidepressant-medications. Accessed October 30, 2025.
