Zoloft vs. Wellbutrin: Which Works Better for Depression?

Major depressive disorder, also known as depression or MDD, is one of the most common mental health conditions in the U.S. There are several ways to treat depression. Antidepressants are one potential treatment option.

Zoloft (sertraline) and Wellbutrin (bupropion) are two common antidepressants. In this article, we’ll take a look at Zoloft versus Wellbutrin and see how they compare.

What is Zoloft?

Zoloft contains the medication sertraline. It belongs to a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) and comes in the forms of tablets and an oral liquid.

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What conditions is Zoloft approved to treat?

Zoloft is FDA-approved to treat many different mental health conditions in adults. These include:

• Depression

• Obsessive-compulsive disorder (OCD)

• Panic disorder

• Post-traumatic stress disorder (PTSD)

• Premenstrual dysphoric disorder (PMDD)

• Social anxiety disorder

Zoloft is also FDA-approved to treat OCD in children and adolescents ages 6 years and older.

How does Zoloft work for depression?

Zoloft works by raising levels of serotonin, a chemical messenger in the brain. Serotonin has many functions in the body. One of those actions is helping to regulate mood and anxiety. Raising levels of serotonin is thought to help relieve depression symptoms.

What is Wellbutrin?

Wellbutrin contains the medication bupropion. Wellbutrin is an atypical antidepressant. But it can also be called a norepinephrine and dopamine reuptake inhibitor (NDRI). Wellbutrin comes as immediate-release (IR), sustained-release (SR), and extended-release (ER or XL) tablets. The IR tablets are only available as a generic medication. The SR and XL tablets come in both brand-name and generic forms.

What conditions is Wellbutrin approved to treat?

Wellbutrin is FDA-approved to treat depression and seasonal affective disorder. The active ingredient in Wellbutrin — bupropion — is used in another medication called Zyban. Zyban is FDA-approved to help people stop smoking.

There are also two other brand names for bupropion: Aplenzin and Forfivo XL. Aplenzin is FDA-approved for depression and seasonal affective disorder. But Forfivo XL is only approved for depression.

How does Wellbutrin work for depression?

It’s not well known how Wellbutrin works for depression. But researchers think it helps raise levels of the chemical messengers norepinephrine and dopamine in the brain. By having more of these chemicals available, Wellbutrin is thought to help improve depression symptoms. 

How are Zoloft and Wellbutrin administered for depression?

The doses for Zoloft and Wellbutrin are quite different from each other. So be sure to follow the instructions on your prescription bottle carefully.

Zoloft dose

Zoloft is usually taken once per day. The typical starting dose for Zoloft is 50 mg once daily. This dose can be slowly raised up to a maximum of 200 mg per day, if needed.

Wellbutrin dose

For Wellbutrin, the dose depends on what type of tablet you’re taking:

• Wellbutrin IR: Most people start with 100 mg by mouth twice daily. This can be raised to a maximum dose of 450 mg per day. This maximum dose would be split into three smaller doses, with at least 6 hours between doses.

• Wellbutrin SR: Most people start with 150 mg by mouth once daily in the morning. After 3 days, your dose could be raised to 150 mg twice daily. There should be at least 8 hours between doses. Doses can be raised to a maximum of 400 mg per day.

• Wellbutrin XL: Most people start with 150 mg by mouth once a day in the morning. This can be raised to a maximum dose of 300 mg once a day.

How effective are Zoloft and Wellbutrin for treating depression?

When compared to a placebo (a pill with no medication in it), studies found Zoloft to be effective for treating depression. Wellbutrin was also found to be effective for depression compared to placebo. While both medications can be effective for treating depression, SSRIs, like Zoloft, are usually tried first.

Several studies have compared Zoloft to Wellbutrin to see if one was better than the other. Many clinical studies have found no significant difference in effectiveness between SSRIs, like Zoloft, and Wellbutrin. A different study also found Zoloft and Wellbutrin to be similarly effective for people who’ve unsuccessfully tried another antidepressant.

What are the known side effects of Zoloft and Wellbutrin?

Here, we’ll list some of the most common side effects of Wellbutrin and Zoloft. But you may still experience some that aren't listed here. If your side effects are bothersome, contact your healthcare provider.

Zoloft also has the potential to cause sexual side effects. This includes erectile dysfunction for men and low sex drive for both men and women. These side effects are rare with Wellbutrin.

What are the serious side effects of Zoloft and Wellbutrin?

Both Zoloft and Wellbutrin have a boxed warning for suicidal thoughts and behavior. Boxed warnings are the strictest warning that the FDA gives to a medication. In studies, the risk of suicide appears to be higher if you’re under 25 years old.

Other serious side effects of Zoloft include:

• Abnormal heart rhythms

• Higher risk of bleeding

• Low sodium levels

• Serotonin syndrome

• Withdrawal symptoms if you suddenly stop Zoloft

• Mania (extreme high energy or excitement) for people with bipolar disorder

Other serious side effects of Wellbutrin include:

• Mental health changes

• Seizures

• High blood pressure

• Mania for people with bipolar disorder

What interactions do Zoloft and Wellbutrin have?

Here, we’ll highlight some of the interactions that Zoloft and Wellbutrin have with other medications. It’s important to keep in mind that these aren’t the only possible interactions that can happen. Always provide a current medication list to your healthcare provider and pharmacist. This way, they can double check for potential interactions.

Zoloft

Some of the important Zoloft interactions to know about include:

• Atomoxetine (Strattera)

• Blood thinners, such as warfarin (Coumadin) and clopidogrel (Plavix)

• Dextromethorphan (Delsym)

• Metoprolol (Lopressor, Toprol XL)

• Monoamine oxidase inhibitors (MAOIs) like selegiline

• Other medications that can cause abnormal heart rhythms, such as amiodarone (Pacerone)

• Other medications that raise serotonin, including tramadol (Ultram) and duloxetine (Cymbalta)

• Phenytoin (Dilantin)

Wellbutrin

Important Wellbutrin interactions to know about include:

• Antipsychotics, such as risperidone (Risperdal) or haloperidol

• MAOIs

• Serotonin and norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine

• SSRIs, including Zoloft

• Tricyclic antidepressants (TCAs), such as amitriptyline

• Beta blockers, such as metoprolol

• Heart rhythm medications, such as flecainide

• Other medications that raise the risk of seizures, like cyclobenzaprine

• Other medications that raise dopamine levels, such as carbidopa/levodopa (Sinemet)

How much do Zoloft and Wellbutrin cost?

Wellbutrin and Zoloft are both relatively inexpensive, and they both have generic versions available. They’re also typically covered by most insurance plans. But if you’re uninsured or underinsured, GoodRx can help you save money.

With a GoodRx coupon, 30 tablets of generic Zoloft 50 mg may cost less than $7 in certain locations. This is compared to the average retail cost of about $30.

Generic Wellbutrin may cost more than Zoloft. But it’s usually still pretty affordable through insurance or with GoodRx. With a GoodRx coupon, 30 tablets of generic Wellbutrin XL 150 mg may cost less than $12 at some pharmacies. To compare, the average retail price is about $70.

Can you take Zoloft and Wellbutrin together for depression?

Since these medications work differently, they can be prescribed together. Although, this is usually reserved for people who’ve already tried an antidepressant without success. However, it’s typical for healthcare providers to try switching people to a different antidepressant before adding a second medication.

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Written by:

Nicole E. Cieri-Hutcherson, PharmD, BCPS, NCMP

Nicole E. Cieri-Hutcherson, PharmD, BCPS, NCMP, has over a decade of experience as a pharmacist, professor, and researcher. She was a full-time clinical professor in the pharmacy practice department at D’Youville School of Pharmacy before subsequently joining the faculty of the pharmacy practice department at the University at Buffalo School of Pharmacy and Pharmaceutical Sciences.

Edited by:

Christina Aungst, PharmD

Christina Aungst, PharmD, is a pharmacy editor for GoodRx. She began writing for GoodRx Health in 2019, transitioning from freelance writer to editor in 2021.

Reviewed by:

Joshua Murdock, PharmD, BCBBS

Joshua Murdock, PharmD, BCBBS, is a licensed pharmacist in Arizona, Colorado, and Rhode Island. He has worked in the pharmacy industry for more than 10 years and currently serves as a pharmacy editor for GoodRx.

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