MS Antidepressant Interactions: What to Know Before Mixing Your Medications

Understanding MS antidepressant interactions is critical if you’re one of the nearly 1 million Americans living with multiple sclerosis. There’s a good chance you’re also dealing with depression—research shows up to 50% of MS patients will experience clinical depression at some point, which is 2-3 times higher than the general population.

So your doctor prescribes an antidepressant. Makes sense, right?

However, here’s what many patients don’t realize: not every antidepressant plays nice with every MS medication. Some combinations are perfectly safe, while others need careful monitoring. Furthermore, a few combinations can cause serious problems if your healthcare team isn’t paying attention.

“Understanding MS antidepressant interactions is something I discuss with patients every day. A patient starts an antidepressant prescribed by their primary care doctor, but nobody checked how it interacts with their Aubagio or Tecfidera. That’s why it’s so important to keep one pharmacy informed about ALL your medications. As a result, we can catch interactions that might slip through the cracks.”
— Julia Kravtsova, PharmD, Head Patient Navigator, QuickRx Specialty Pharmacy

This comprehensive guide to MS antidepressant interactions breaks down what you need to know about mixing antidepressants with your MS treatment—so you can advocate for yourself at your next appointment.

Why Depression Is So Common in MS (And Why MS Antidepressant Interactions Matter)

Before we dive into drug interactions, let’s first understand why this matters so much.

According to research published in the Journal of Neurology, Neurosurgery & Psychiatry, depression in MS isn’t just about feeling sad after a tough diagnosis. Instead, it’s often caused by:

• Brain lesions affecting mood-regulating areas
• Chronic inflammation that impacts neurotransmitter systems
• HPA axis dysfunction (your body’s stress response system going haywire)
• The emotional toll of living with an unpredictable chronic illness

When left untreated, depression doesn’t just make you feel terrible—it can actually make your MS worse. For example:

• You’re less likely to stick with your disease-modifying therapy
• Fatigue and cognitive symptoms get amplified
• Quality of life tanks significantly
• Risk of suicide increases (MS patients have elevated suicide rates)

Bottom line: Treating depression is critical for MS patients. However, understanding MS antidepressant interactions ensures it’s done safely alongside your disease-modifying therapies.

The Major Classes of Antidepressants Used in MS

Before we dive into specific MS antidepressant interactions, here’s a quick overview of the antidepressants most commonly prescribed to MS patients:

SSRIs (Selective Serotonin Reuptake Inhibitors)

These medications are usually the first-line treatment for depression in MS because they’re generally well-tolerated.

• Sertraline (Zoloft)
• Fluoxetine (Prozac)
• Paroxetine (Paxil)
• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Fluvoxamine (Luvox)

SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

These are particularly good for depression PLUS pain or fatigue. As a result, they’re often chosen when patients have multiple symptoms.

• Duloxetine (Cymbalta)
• Venlafaxine (Effexor)
• Desvenlafaxine (Pristiq)

Other Antidepressant Options

Additionally, there are several other antidepressants that may be considered:

• Bupropion (Wellbutrin) – helpful for fatigue, with lower sexual side effects
• Mirtazapine (Remeron) – good for insomnia and appetite issues
• Tricyclic antidepressants (TCAs) – an older class with more side effects

MS Antidepressant Interactions: The Complete Medication-by-Medication Breakdown

Now let’s get into the specifics. Below, I’ve organized interactions by MS medication so you can quickly find what applies to you.

Teriflunomide (Aubagio) + Antidepressants

Primary concern: LIVER FUNCTION

Teriflunomide is processed by the liver and can cause elevated liver enzymes. Similarly, several antidepressants also affect the liver, creating potential for compounded hepatotoxicity (liver damage).

What to do: If you’re on Aubagio and need an antidepressant, sertraline is often a good starting point. However, if duloxetine is preferred (especially for pain), your doctor should monitor liver enzymes more frequently.

Interferons (Rebif, Avonex, Betaseron, Plegridy) + Antidepressants

Primary concerns: LIVER FUNCTION + HISTORICAL DEPRESSION QUESTIONS

Interferons can cause elevated liver enzymes. Additionally, there was historical concern that interferons might worsen depression—though newer research (including the large BEYOND trial) suggests this risk was overstated.

Dimethyl Fumarate (Tecfidera) & Diroximel Fumarate (Vumerity) + Antidepressants

Primary concern: MINIMAL—which is good news!

Fortunately, Tecfidera and Vumerity have relatively few significant interactions with common antidepressants.

Note: Tecfidera can cause flushing and GI upset. Interestingly, some patients find these side effects worsen anxiety. If that’s you, treating the underlying anxiety/depression may actually help you tolerate your MS medication better.

Fingolimod (Gilenya) + Antidepressants

Primary concern: HEART RHYTHM EFFECTS

Gilenya can cause bradycardia (slow heart rate) and QT prolongation, especially during the first dose. Consequently, some antidepressants that also affect heart rhythm require careful consideration.

Interesting note: Research shows fingolimod actually shares some mechanisms with the tricyclic antidepressant desipramine—both inhibit an enzyme called acid sphingomyelinase. However, this doesn’t mean you should take them together (the cardiac risks still apply), but it shows how complex these interactions can be.

Glatiramer Acetate (Copaxone, Glatopa) + Antidepressants

Primary concern: MINIMAL—great news for Copaxone users!

Because glatiramer acetate works through immune modulation rather than being processed by the liver or affecting the heart, it has very few interactions with antidepressants. Consequently, most options are available to you.

Natalizumab (Tysabri) + Antidepressants

Primary concern: MINIMAL—another favorable profile

Tysabri is given as an IV infusion, which means it doesn’t significantly interact with oral antidepressants through liver metabolism or cardiac pathways. Therefore, all major antidepressant classes are generally safe with Tysabri.

Ocrelizumab (Ocrevus) + Antidepressants

Primary concern: MINIMAL—similar to Tysabri

Like Tysabri, Ocrevus is an infusion therapy with few direct drug-drug interactions with antidepressants. As a result, all major antidepressant classes are generally safe with Ocrevus.

Cladribine (Mavenclad) + Antidepressants

Primary concern: IMMUNE SUPPRESSION TIMING

Mavenclad causes significant lymphocyte reduction. While there aren’t major direct interactions with antidepressants, the overall immune suppression means you should discuss any new medications with your neurologist. Consequently, coordination with your healthcare team is especially important.

Quick Reference Guide: MS Antidepressant Interactions by Medication

Based on the interaction profiles above, here’s a simplified guide to help you navigate your options:

“When reviewing MS antidepressant interactions, sertraline keeps showing up as a safe option across the board—and there’s a reason. It’s well-studied in MS, has a favorable side effect profile, and doesn’t cause major issues with liver or heart. Therefore, if you’re starting depression treatment and don’t know where to begin, it’s often a solid first choice to discuss with your doctor.”
— Julia Kravtsova, PharmD, Head Patient Navigator, QuickRx Specialty Pharmacy

Red Flags: Dangerous MS Antidepressant Interactions to Watch For

When taking an antidepressant alongside your MS medication, it’s essential to watch for these warning signs of potential MS antidepressant interactions:

5 Questions to Ask About MS Antidepressant Interactions

Before starting any antidepressant, make sure to have this conversation about potential MS antidepressant interactions with your providers:

1. “Have you checked for interactions with my MS medication?” – Make sure they have your complete med list.
2. “Do I need any baseline labs?” – Liver function tests may be needed, especially with Aubagio or interferons.
3. “What side effects should I watch for?” – Know what’s expected vs. what’s a red flag.
4. “How long until I should feel better?” – Most antidepressants take 4-6 weeks for full effect.
5. “What if this one doesn’t work?” – Having a backup plan is important.

Beyond Medication: Other Depression Treatments That Work

Antidepressants aren’t the only option for managing depression with MS. In fact, research supports these approaches for MS-related depression:

Cognitive Behavioral Therapy (CBT)

This is the most-studied psychotherapy for depression in MS. It can be done in-person, by phone, or online. Furthermore, it often works best when combined with medication.

Exercise and Physical Activity

Physical activity has proven benefits for both MS symptoms and depression. Even gentle exercise like walking, swimming, or yoga can help significantly.

Mindfulness-Based Interventions

Mindfulness-based stress reduction (MBSR) and similar programs show promise for MS patients with depression. Additionally, many patients find these techniques help with anxiety as well.

Support Groups and Community

Connecting with others who understand MS can reduce isolation—which is a major contributor to depression. As a result, many patients find support groups invaluable.

The Cost Factor: Affording Your MS and Depression Treatment

Let’s be real: managing MS AND depression often means multiple medications. Between your disease-modifying therapy, symptom medications, and now an antidepressant, costs can add up fast.

Furthermore, the financial stress of affording treatment can actually worsen depression—creating a vicious cycle that’s hard to break.

That’s where MS medication copay assistance comes in to help.

At QuickRx Specialty Pharmacy, we specialize in helping MS patients access copay cards, patient assistance programs, and manufacturer savings to reduce out-of-pocket costs—often to $0.

Our MS Copay Assistance Services Include:

We help patients access copay cards and patient assistance programs for all major MS medications, including:

• Ampyra (dalfampridine) copay card – Helps improve walking ability in MS patients
• Aubagio (teriflunomide) copay assistance – Once-daily oral disease-modifying therapy
• Copaxone (glatiramer acetate) copay card – Injectable disease-modifying therapy
• Gilenya (fingolimod) copay assistance – Once-daily oral medication for relapses
• Mavenclad (cladribine) patient assistance – Short-course oral therapy for highly active MS
• Tecfidera (dimethyl fumarate) copay card – Twice-daily oral disease-modifying therapy
• Vumerity (diroximel fumarate) copay assistance – Helps reduce relapses with better GI tolerability

Additionally, we provide:

• Coordination with your insurance for prior authorizations
• Navigation of manufacturer patient assistance programs
• Foundation grant applications
• Ongoing refill support and reminders
• Direct coordination with your neurologist’s office

Visit our Multiple Sclerosis Copay Assistance page to learn more about how we help MS patients access affordable treatment.

Additionally, we help patients find savings on antidepressants and other prescriptions—because your mental health matters too.

“Nobody should have to choose between their MS treatment and their mental health because of cost. We work with every patient individually to find programs that can make both affordable. As a result, patients are often shocked to learn they qualify for assistance they didn’t know existed.”
— Julia Kravtsova, PharmD, Head Patient Navigator, QuickRx Specialty Pharmacy

Ready to explore your copay assistance options?

Call: (917) 830-2525
Toll-Free: (800) 496-6111

Or visit our MS copay assistance page to get started.

Frequently Asked Questions About MS Antidepressant Interactions

Can I take any antidepressant with my MS medication?

Not necessarily—MS antidepressant interactions vary depending on your specific medications. While many combinations are safe, some require caution or monitoring. The safest approach is to work with both your neurologist and a pharmacist who can review your complete medication list for interactions. Generally speaking, sertraline (Zoloft) has a good safety profile across most MS medications.

Will antidepressants interfere with how well my MS treatment works?

In most cases, no. Antidepressants and MS disease-modifying therapies work through different mechanisms. In fact, treating depression may actually improve your MS outcomes by helping you stick with your treatment plan and maintain healthy habits.

My doctor prescribed duloxetine but I’m on Aubagio. Should I be worried?

This combination requires monitoring but isn’t necessarily contraindicated. Both medications can affect the liver, so your doctor should order baseline liver function tests and monitor them periodically. However, if your liver enzymes stay normal, the combination may be fine for you. Don’t stop either medication without talking to your doctor first.

I’m on Gilenya and was told to avoid certain antidepressants. Why is that?

Gilenya can affect heart rhythm, particularly causing slow heart rate and QT prolongation. Similarly, some antidepressants (especially citalopram and tricyclic antidepressants) also affect heart rhythm. As a result, combining them increases cardiac risks. Safer options with Gilenya include sertraline and bupropion.

Do MS patients need different doses of antidepressants?

Research suggests MS patients may respond to lower doses than the general population. Therefore, the general approach is “start low, go slow”—beginning with a lower dose and gradually increasing based on response and tolerability. This approach also helps minimize side effect risks.

Can antidepressants help with MS fatigue too?

Potentially, yes. SNRIs like duloxetine and bupropion (Wellbutrin) have energizing properties that may help with fatigue. However, fatigue improvement varies by individual. SSRIs are generally neutral regarding fatigue, while some antidepressants (TCAs, mirtazapine) can be sedating.

What if my antidepressant makes my MS symptoms worse?

If this happens, report any changes to your healthcare team immediately. Some antidepressant side effects (like cognitive dulling with paroxetine, or sedation with mirtazapine) can mimic or worsen MS symptoms. The good news is there are many antidepressant options—so if one doesn’t work well for you, another likely will.

Should I tell my neurologist if I’m feeling depressed?

Absolutely, yes. Depression is so common in MS that many neurologists screen for it at every visit. Your neurologist needs to know about your mental health to provide coordinated care, watch for medication interactions, and ensure you’re getting comprehensive treatment.

How does QuickRx help with MS medication costs?

QuickRx Specialty Pharmacy provides free copay assistance services specifically for MS patients. We help you enroll in manufacturer copay cards, patient assistance programs, and foundation grants. Additionally, our team navigates insurance requirements and coordinates with your healthcare providers. As a result, many patients reduce their out-of-pocket costs to $0. Call (917) 830-2525 to learn more about MS copay assistance options.

Is it safe to take an antidepressant while pregnant and on MS medication?

This requires careful discussion with your healthcare team. Both MS medications and antidepressants have varying safety profiles in pregnancy. Some are relatively safe while others should be avoided. Therefore, if you’re planning pregnancy or discover you’re pregnant, contact your neurologist and OB/GYN immediately to review your medications.

HIPAA Compliance Notice: QuickRx Specialty Pharmacy protects your health information in accordance with HIPAA regulations. This blog contains general educational information only.

Medical References

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4. Solaro C, Trabucco E, Messmer Uccelli M. Duloxetine is effective in treating depression in multiple sclerosis patients: an open-label multicenter study. Clin Neuropharmacol. 2013;36(4):114-6.
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8. National Multiple Sclerosis Society. Depression and Multiple Sclerosis. Accessed December 2025.
9. Teriflunomide (Aubagio) Prescribing Information. Sanofi Genzyme. FDA Label.
10. Fingolimod (Gilenya) Prescribing Information. Novartis. FDA Label.