Lexapro and Wellbutrin: A Psychiatrist’s Guide to Combination Therapy

This content is for informational purposes and not a substitute for medical advice.

Quick Answer

Can you take Lexapro and Wellbutrin together? Yes, many psychiatrists prescribe Lexapro (escitalopram) and Wellbutrin (bupropion) together as combination therapy for treatment-resistant depression. While both medications can be safely combined under medical supervision, this approach requires careful monitoring for potential interactions and side effects. The combination targets different neurotransmitter systems, Lexapro increases serotonin while Wellbutrin boosts dopamine and norepinephrine, potentially providing more comprehensive symptom relief than either medication alone.

When you’re dealing with depression that hasn’t fully responded to a single medication, your psychiatrist might suggest combining treatments. One increasingly common approach involves pairing Lexapro and Wellbutrin, two antidepressants that work through different mechanisms in your brain.

This combination therapy isn’t right for everyone, but for many people with depression, it can provide significant relief when individual medications fall short. Understanding how these medications work together, and their potential risks, can help you have more informed conversations with your healthcare provider.

Understanding Each Medication

Lexapro (Escitalopram): The SSRI

Lexapro belongs to a class of antidepressants called selective serotonin reuptake inhibitors (SSRIs) [1]. This medication works by preventing your brain from reabsorbing serotonin, a neurotransmitter that helps regulate mood and emotions. By keeping more serotonin available in your brain, Lexapro can help reduce symptoms of depression and anxiety.

FDA-approved uses for Lexapro:

• Major depressive disorder in adults and adolescents
• Generalized anxiety disorder in adults

Common benefits:

• Reduces anxiety symptoms
• Improves mood stability
• Generally well-tolerated
• Extensive safety data

Important considerations:

• May cause sexual side effects
• Risk of withdrawal symptoms if stopped abruptly
• FDA boxed warning for increased suicidal thoughts in children, adolescents, and young adults [1]

Wellbutrin (Bupropion): The Atypical Antidepressant

Wellbutrin works differently than SSRIs. It’s classified as a norepinephrine-dopamine reuptake inhibitor (NDRI), meaning it primarily increases levels of norepinephrine in your brain, with weaker effects on dopamine [2]. These neurotransmitters are associated with energy, motivation, focus, and pleasure.

FDA-approved uses for Wellbutrin:

• Major depressive disorder
• Seasonal affective disorder
• Smoking cessation

Common benefits:

• Increases energy and motivation
• Less likely to cause weight gain
• Lower risk of sexual side effects
• May improve focus and concentration

Important considerations:

• May cause anxiety, insomnia, or elevated blood pressure
• Risk of seizures, especially at higher doses
• FDA boxed warning for increased suicidal thoughts in children, adolescents, and young adults [2]

Lexapro vs. Wellbutrin: Key Differences at a Glance

Factor	Lexapro (Escitalopram)	Wellbutrin (Bupropion)
Drug Class	SSRI	NDRI (Atypical)
Primary Target	Serotonin	Norepinephrine + Dopamine
Best For	Anxiety + Depression	Energy + Motivation
Common Side Effects	Sexual dysfunction, weight gain	Insomnia, anxiety initially
Weight Impact	May cause weight gain	Often weight neutral/loss
Sexual Side Effects	Common	Rare
Seizure Risk	Very low	Low but higher than SSRIs
Starting Dose	10mg daily	150mg daily (SR/XL)
FDA Approval	Depression, anxiety	Depression, SAD, smoking cessation

When Psychiatrists Consider Combination Therapy

Combination therapy with Lexapro and Wellbutrin isn’t typically a first-line treatment. Psychiatrists usually consider this approach in several specific situations:

Treatment-Resistant Depression

Research from the landmark STAR*D study found that only 28.6% of patients achieved remission with initial SSRI treatment [3]. For the significant portion of people who don’t respond adequately to a single antidepressant, combination therapy may offer additional benefits.

Incomplete Symptom Relief

Some patients experience partial improvement with one medication but continue struggling with specific symptoms. For example:

• Persistent fatigue and low energy on Lexapro alone
• Continued anxiety symptoms with Wellbutrin alone
• Sexual side effects from SSRI treatment

Complementary Symptom Targeting

The combination can address different aspects of depression simultaneously:

• Lexapro targets mood regulation and anxiety
• Wellbutrin addresses energy, motivation, and cognitive symptoms

How the Combination Works

When prescribed together, Lexapro and Wellbutrin target three major neurotransmitter systems simultaneously:

Serotonin (from Lexapro): Helps with mood stability, anxiety reduction, and emotional regulation

Dopamine and Norepinephrine (from Wellbutrin): Support energy levels, motivation, focus, and pleasure response

This multi-target approach can be particularly beneficial for people whose depression involves both emotional symptoms (sadness, anxiety) and motivational symptoms (low energy, lack of interest) [4].

Clinical Evidence and Effectiveness

Several studies support the effectiveness of combining escitalopram and bupropion:

Research Findings

Clinical evidence supports the effectiveness of combining escitalopram and bupropion in certain situations. The landmark STAR*D study found that when bupropion was added to patients who didn’t respond adequately to initial SSRI treatment, 29.7% achieved remission [3].

Additional research demonstrates that combination therapy may be particularly beneficial for patients with treatment-resistant depression, offering complementary mechanisms of action that target multiple neurotransmitter systems simultaneously [4].

Patient Outcomes

Clinical studies indicate that combination therapy may offer:

• Faster onset of antidepressant effects
• Higher remission rates in treatment-resistant cases
• Reduced sexual side effects compared to SSRI monotherapy
• Better energy and motivation compared to SSRI alone

However, individual responses vary significantly, and combination therapy requires careful medical supervision to monitor for both benefits and potential adverse effects [5].

Potential Risks and Safety Considerations

While generally safe when properly monitored, combining Lexapro and Wellbutrin does carry some risks that require careful consideration:

Increased Seizure Risk

Both medications can lower seizure threshold, and combining them may increase this risk [6]. The risk is higher in people with:

• History of seizures or head trauma
• Eating disorders
• Alcohol or substance withdrawal
• Brain tumors or other neurological conditions

Drug Interaction Effects

Co-administration may increase escitalopram levels and seizure risk, requiring medical supervision and possible dosing adjustments [7]. This interaction necessitates careful dosing and monitoring.

Serotonin Syndrome (Rare)

While uncommon, there’s a rare but potential risk of serotonin syndrome when combining these medications, especially at higher doses [8]. Symptoms include confusion, rapid heart rate, high fever, and muscle rigidity.

Enhanced Side Effects

Common side effects may be more pronounced when medications are combined:

• Sleep disturbances
• Increased anxiety (initially)
• Dry mouth
• Nausea
• Changes in appetite

What to Expect: Monitoring and Management

When your psychiatrist prescribes Lexapro and Wellbutrin together, expect close monitoring, especially during the first few weeks:

Initial Monitoring Phase

• Weekly check-ins for the first month
• Gradual dosing starting with lower doses
• Side effect tracking to identify any concerning symptoms
• Blood pressure monitoring as Wellbutrin can increase blood pressure

Typical Dosing Approach

Most psychiatrists start conservatively:

• Lexapro: Usually 10mg daily (may adjust to 5-20mg)
• Wellbutrin: Often 150mg daily of sustained-release or extended-release formulation (may increase to 300-450mg)

Long-term Management

Once stabilized, patients typically have:

• Monthly follow-up appointments
• Regular assessment of effectiveness
• Ongoing side effect monitoring
• Periodic evaluation of continued need for combination therapy

Alternatives to Lexapro-Wellbutrin Combination

If combination therapy isn’t appropriate or effective, other options include:

Other Combination Strategies

• SSRI + mirtazapine for patients with sleep and appetite issues
• SSRI + aripiprazole for treatment-resistant depression
• SNRI monotherapy (duloxetine, venlafaxine) targeting multiple neurotransmitters

Non-Medication Approaches

• Transcranial Magnetic Stimulation (TMS) for treatment-resistant depression
• Cognitive Behavioral Therapy (CBT) as adjunct to medication
• Lifestyle interventions including exercise and sleep optimization

Who Should Avoid This Combination

Certain individuals should not take Lexapro and Wellbutrin together:

• People with seizure disorders or high seizure risk
• Those with uncontrolled high blood pressure
• Individuals with eating disorders
• People taking MAOIs or within 14 days of stopping MAOIs
• Those with severe liver or kidney disease

Making the Decision: Questions for Your Provider

If you’re considering combination therapy, discuss these questions with your psychiatrist:

1. Have I given my current medication adequate time and dosing?
2. What specific symptoms might combination therapy address?
3. What are my personal risk factors for side effects?
4. How will we monitor for potential complications?
5. What are realistic expectations for improvement?
6. Are there alternative approaches to consider first?

Final Thoughts

Take the First Step Toward Comprehensive Depression Care

Combination therapy with Lexapro and Wellbutrin represents an important option for people whose depression hasn’t fully responded to single medications. While this approach requires careful medical supervision and monitoring, many patients find significant relief when targeting multiple neurotransmitter systems simultaneously.

Whether you’re considering Lexapro and Wellbutrin combination therapy or exploring other treatment options, PsychPlus is here to provide expert psychiatric care tailored to your unique needs. Our experienced psychiatrists understand the complexities of treatment-resistant depression and work with you to develop personalized treatment plans that may include medication combinations, therapy, and innovative treatments like TMS.

With same-day and next-day appointments available, both in-person and online, and acceptance of most insurance plans including Medicare and Medicaid, getting expert psychiatric care has never been more accessible. Don’t let treatment-resistant depression control your life, take the first step toward comprehensive care that addresses all aspects of your mental health.

Ready to explore your treatment options? Contact PsychPlus today to schedule a consultation with one of our board-certified psychiatrists who can help determine if combination therapy or other advanced treatments might be right for you.

Frequently Asked Questions

Can Lexapro and Wellbutrin be taken at the same time of day?

Yes, both medications can typically be taken together. Many people take Lexapro in the morning and Wellbutrin with breakfast to minimize sleep disruption, but your psychiatrist will provide specific timing recommendations based on your individual response.

How long does it take to see results from the combination?

Most people begin noticing some benefits within 2-4 weeks, with full effects typically seen by 6-8 weeks. However, some patients may experience improvements in energy and motivation from Wellbutrin within the first week.

Will I gain weight on this combination?

Weight gain is less likely with this combination compared to Lexapro alone, as Wellbutrin often causes weight loss or weight neutrality, potentially offsetting any weight gain from Lexapro.

Can I drink alcohol while taking both medications?

Alcohol should be avoided or strictly limited when taking this combination, as it can increase the risk of seizures and interfere with the medications’ effectiveness. Always discuss alcohol use with your psychiatrist.

What should I do if I miss a dose of either medication?

Take the missed dose as soon as you remember, unless it’s almost time for your next dose. Never double up on doses. If you frequently forget doses, discuss reminder strategies with your healthcare provider.

Is this combination safe long-term?

With proper monitoring, many people safely take this combination for extended periods. Your psychiatrist will regularly evaluate the ongoing need for combination therapy and may adjust or simplify your regimen over time.

References:

[1] Food and Drug Administration. (2023). Lexapro (escitalopram oxalate) prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021323s055,021365s039lbl.pdf

[2] Food and Drug Administration. (2017). Wellbutrin (bupropion hydrochloride) prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018644s052lbl.pdf

[3] Trivedi, M. H., et al. (2006). Medication augmentation after the failure of SSRIs for depression. New England Journal of Medicine, 354(12), 1243-1252. https://www.nejm.org/doi/full/10.1056/NEJMoa052964

[4] Rush, A. J., et al. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. American Journal of Psychiatry, 163(11), 1905-1917. https://ajp.psychiatryonline.org/doi/10.1176/ajp.2006.163.11.1905

[5] Blier, P., et al. (2010). Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. American Journal of Psychiatry, 167(3), 281-288. https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2009.09020186

[6] Huecker MR, Smiley A, Saadabadi A. Bupropion. [Updated 2024 Sep 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470212/

[7] Drugs.com. (2024). Drug Interaction Report: Lexapro and Wellbutrin. https://www.drugs.com/drug-interactions/lexapro-with-wellbutrin-1013-565-440-203.html

[8] Munhoz, R. P. (2004). Serotonin syndrome induced by a combination of bupropion and SSRIs. Clinical Neuropharmacology, 27(5), 219-222. https://pubmed.ncbi.nlm.nih.gov/15602102/