Wellbutrin (bupropion) is not an SSRI—it is an NDRI (norepinephrine and dopamine reuptake inhibitor), making it fundamentally different from selective serotonin reuptake inhibitors like Prozac or Zoloft.
Unlike SSRIs that work by increasing serotonin levels, Wellbutrin works by blocking your body from reabsorbing dopamine and norepinephrine, resulting in higher levels of both of these chemicals. This unique mechanism gives Wellbutrin distinct advantages and side effect profiles compared to traditional SSRIs.
Key Takeaways
Wellbutrin is an NDRI, not an SSRI: It works by increasing norepinephrine and dopamine levels rather than serotonin, making it fundamentally different from SSRIs like Prozac or Zoloft.
Different side effect profile: Wellbutrin typically causes fewer sexual side effects and weight gain compared to SSRIs, but may have a slightly higher seizure risk and can cause insomnia due to its stimulating properties.
Equally effective treatment option: Research shows Wellbutrin is as effective as SSRIs for treating depression, making it a valuable alternative or addition to treatment, especially for people who haven't responded to or can't tolerate SSRIs.
What Is Wellbutrin?
Wellbutrin is an antidepressant medication that has received FDA approval for the treatment of depression and seasonal affective disorder and as an aid for smoking cessation.
Since its approval in 1985, bupropion has been utilized off-label for various conditions, including antidepressant-induced sexual dysfunction, depression associated with bipolar disorder, obesity, and ADHD in pediatric patients.
Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs).
How Common Are Different Types of Antidepressants?
Antidepressants are used by more than 1 in 10 people in the United States and many other countries. SSRIs are commonly used as first-line treatments for depression, meaning they are the medications that healthcare providers prescribe first when treating people with clinical depression. However, many people may use an NDRI like bupropion instead due to the effects on norepinephrine and dopamine levels as well as fewer side effects.
What Makes Wellbutrin Different from SSRIs?
Understanding the key differences between Wellbutrin and SSRIs helps explain why healthcare providers might choose one over the other.
Mechanism of Action
Bupropion acts as a norepinephrine–dopamine reuptake inhibitor (NDRI) and a nicotinic receptor antagonist, while SSRIs work exclusively on serotonin. NDRIs do not affect serotonin, that third chemical that can guide emotions, whereas SSRIs focus solely on boosting serotonin levels by blocking reuptake.
Targeted Neurotransmitters
Wellbutrin affects the norepinephrine and dopamine neurotransmitters. Norepinephrine is thought to play a role in the body's stress response and helps to regulate sleep, alertness, and blood pressure. Dopamine plays a key role in movement and affects motivation, perception of reality, and the ability to experience pleasure.
Clinical Effects
Bupropion has several features that distinguish it from other antidepressants: it does not usually cause sexual dysfunction, it is not associated with weight gain and sleepiness, and it is more effective than SSRIs at improving symptoms of hypersomnia and fatigue.
Understanding Antidepressant Classifications
To better understand where Wellbutrin fits, it's helpful to know the main categories of antidepressants.
SSRIs (Selective Serotonin Reuptake Inhibitors)
SSRIs increase serotonin levels in the brain by blocking serotonin reuptake. Common examples include fluoxetine (Prozac), citalopram (Celexa), and sertraline (Zoloft). They're often the first-line treatment for depression due to their generally favorable side effect profile.
SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)
SNRIs increase serotonin and norepinephrine levels by blocking the reuptake of both neurotransmitters. Examples include duloxetine (Cymbalta) and venlafaxine (Effexor).
NDRIs (Norepinephrine-Dopamine Reuptake Inhibitors)
Bupropion is currently the only available NDRI shown to increase dopamine neurotransmission in both the nucleus accumbens and the prefrontal cortex. NDRIs block the transport of norepinephrine and dopamine back into the brain cells that released them.
How Effective Is Wellbutrin Compared to SSRIs?
Research demonstrates that Wellbutrin is as effective as SSRIs for treating depression, but with different advantages and considerations.
Clinical Effectiveness
While it has comparable effectiveness to typical first-line options for the treatment of depression, such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications.
Treatment-Resistant Depression
A 2005 review that compared bupropion to SSRIs found that both medications were equally effective in treating depression but the major difference was that SSRIs were more likely to cause sexual dysfunction. NDRIs may often be used as an SSRI alternative or as a secondary medication in combination with an SSRI or SNRI.
Combination Therapy
A 2016 systematic review of bupropion, which examined 51 studies, supported its use as an antidepressant prescribed on its own or with another antidepressant.
Side Effect Differences: Wellbutrin vs SSRIs
The different mechanisms of action between Wellbutrin and SSRIs result in notably different side effect profiles.
Common SSRI Side Effects
Common side effects from taking SSRIs may include:
Sexual dysfunction (reduced libido, difficulty reaching orgasm)
Weight gain
Drowsiness or sedation
Nausea and gastrointestinal issues
Sleep disturbances
Common NDRI Side Effects
While NDRIs can and do come with side effects, a particularly notable difference is the lack of sexual side effects NDRIs carry, which are common and often distressing for clients taking SSRIs. Common NDRI side effects include:
Dry mouth
Insomnia or sleep disturbances
Headache
Nausea
Constipation
Weight loss (rather than weight gain)
Seizure Risk
Bupropion may increase the risk of seizures. There is a greater risk with higher doses. The incidence of seizures reported in the product information for Wellbutrin SR and Zyban is 0.1% for doses up to 300 mg/day.
When Might a Doctor Choose Wellbutrin Over an SSRI?
Healthcare providers consider several factors when deciding between Wellbutrin and SSRIs.
Specific Symptoms
If someone is struggling with low energy or lack of motivation, certain NDRIs may be a good option to give them more pep in their step to get through the day. NDRIs tend to be more stimulating given the chemicals they target.
Side Effect Considerations
Wellbutrin might be preferred when:
Sexual side effects from SSRIs are problematic
Weight gain is a concern
Sedation from other antidepressants interferes with daily functioning
Studies have shown that bupropion is less likely to cause sexual side effects than other antidepressant medications
Treatment History
Many people may use an NDRI like bupropion instead due to the effects on norepinephrine and dopamine levels as well as fewer side effects. Wellbutrin is often considered when SSRIs haven't been effective or have caused intolerable side effects.
Can Wellbutrin and SSRIs Be Used Together?
Yes, Wellbutrin and SSRIs can sometimes be combined under medical supervision.
Combination Benefits
A NDRI can be added to a client's treatment plan to augment the effects of an SSRI or improve symptoms beyond the use of an SSRI alone. Sometimes they may be used to counteract the side effects of each, to target symptoms that persist despite the use of the initial medication.
Important Considerations
Serotonin syndrome has been reported when bupropion is co-administered with drugs known to be associated with serotonin syndrome, including selective serotonin reuptake inhibitors (SSRIs). If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised.
Safety Considerations and Contraindications
Understanding when Wellbutrin might not be appropriate is important for safe treatment.
Who Should Avoid Wellbutrin
As it promotes weight loss, it is contraindicated in patients with eating disorders. Other contraindications include:
History of seizure disorders
Current or prior diagnosis of bulimia or anorexia nervosa
Abrupt discontinuation of alcohol or sedatives
Use of MAOIs within 14 days
Monitoring Requirements
Bupropion may increase your blood pressure or make it worse if you have a history of high blood pressure. Healthcare providers should monitor blood pressure during treatment.
Medical Disclaimer
This article is for educational purposes only and does not constitute medical advice. The information provided should not replace consultation with a qualified healthcare provider. Individual responses to medications can vary significantly, and what applies to one person may not be safe for another.
Always consult with your doctor or pharmacist before making any decisions about medication changes, discontinuation, or interactions with other substances. If you're experiencing concerning symptoms or side effects, please seek professional help from a healthcare provider. In case of a medical emergency, contact your local emergency services immediately or call 911. For mental health emergencies, contact the National Suicide Prevention Lifeline at 988.
Important: This information is not a substitute for professional medical advice. Never stop taking prescribed medication or make changes to your treatment plan without consulting your healthcare provider first. Your safety and well-being are the top priorities.
