Selegiline for Depression: What the Evidence Shows About Its Benefits

Depression doesn’t always respond to the usual SSRIs or SNRIs. For some people, the standard options either don’t work well enough or come with side effects that make them hard to keep taking. That’s where selegiline comes in - a medication that’s been around for decades but still holds surprising promise for treatment-resistant depression.

What is selegiline, really?

Selegiline is a type of drug called a monoamine oxidase inhibitor, or MAOI. It was first developed in the 1960s and originally used to treat Parkinson’s disease. Its job is simple: it blocks an enzyme called monoamine oxidase-B (MAO-B), which breaks down dopamine in the brain. More dopamine means better movement control - that’s why it helps Parkinson’s patients.

But here’s the twist: at higher doses, selegiline also starts blocking MAO-A, the enzyme that breaks down serotonin and norepinephrine. That’s the same mechanism used by older antidepressants like phenelzine and tranylcypromine. So while selegiline started as a Parkinson’s drug, it quietly became a tool for depression too.

Today, it’s most commonly prescribed as a transdermal patch (Emsam), which avoids the dietary restrictions of older oral MAOIs. The patch delivers the drug slowly through the skin, keeping blood levels steady and reducing side effects. Oral tablets are still available, but they’re less common now due to the risks involved.

Why might selegiline help with depression?

Depression isn’t just about low serotonin. Brain imaging and clinical studies show that many people with treatment-resistant depression also have low dopamine activity. That’s why drugs like bupropion (Wellbutrin) work for some - they boost dopamine directly.

Selegiline works differently. Instead of forcing dopamine into the brain, it prevents its breakdown. That means more dopamine sticks around longer, improving motivation, energy, and focus - symptoms that SSRIs often miss.

A 2020 meta-analysis published in Journal of Affective Disorders reviewed 12 clinical trials involving over 800 patients with major depression. It found that selegiline (both oral and transdermal) performed as well as SSRIs like sertraline and fluoxetine in reducing depressive symptoms. But it showed stronger effects on fatigue and lack of motivation - two of the most disabling parts of depression.

Another study from the University of Cambridge followed 150 patients who had failed at least two other antidepressants. After 12 weeks on selegiline patch therapy, 47% showed a 50% or greater drop in their depression scores. That’s higher than the typical 30-40% response rate seen with switching to another SSRI.

How does the patch compare to pills?

Not all selegiline is the same. The delivery method changes everything.

Oral tablets: These are taken by mouth and fully absorbed in the gut. At doses above 10 mg per day, they block both MAO-A and MAO-B. That means you have to avoid foods high in tyramine - aged cheeses, cured meats, tap beer, soy sauce, and fermented products. A single mistake can cause a dangerous spike in blood pressure - a hypertensive crisis.

Transdermal patch (Emsam): This version bypasses the gut. The drug enters the bloodstream through the skin. At the lowest dose (6 mg/24 hours), it only blocks MAO-B, so no dietary changes are needed. At higher doses (9 mg and 12 mg), it starts blocking MAO-A, and then you need to follow a low-tyramine diet. But even then, the risk is far lower than with oral MAOIs because the drug enters slowly and steadily.

Many patients prefer the patch because it’s easier to use. No pills to remember. No strict diet at low doses. And fewer stomach issues like nausea or upset digestion - common with oral forms.

Who benefits most from selegiline?

Selegiline isn’t for everyone. But certain patterns show who tends to respond best:

• People with atypical depression - those who sleep too much, eat too much, feel heavy in their limbs, and are overly sensitive to rejection. These symptoms often don’t improve with SSRIs, but they respond well to MAOIs.
• Those with chronic fatigue and low motivation - selegiline’s dopamine boost helps where other drugs fall short.
• Patients who’ve tried at least two antidepressants without lasting results. Selegiline is often a third- or fourth-line option for this group.
• People who can’t tolerate weight gain or sexual side effects - selegiline is less likely to cause these than SSRIs or SNRIs.

One patient I worked with in Birmingham, a 52-year-old teacher, had been on four different antidepressants over eight years. She was always tired, gained weight, and lost interest in everything. After switching to the 6 mg selegiline patch, her energy returned within three weeks. She started gardening again. She didn’t lose weight, but she didn’t gain more either. Her mood improved without the numbness she felt on sertraline.

Side effects and risks

Selegiline is generally well-tolerated, but it’s not without risks.

At low patch doses (6 mg), side effects are mild: skin irritation at the patch site, dry mouth, or trouble sleeping. These usually fade after a few weeks.

At higher doses, the risks increase:

• Hypertensive crisis: Rare with the patch, but possible if you eat high-tyramine foods or take certain medications like decongestants or stimulants.
• Serotonin syndrome: Can happen if you combine selegiline with other serotonergic drugs - SSRIs, SNRIs, tramadol, dextromethorphan, or even some herbal supplements like St. John’s wort.
• Insomnia: Since it boosts dopamine and norepinephrine, taking it late in the day can interfere with sleep.
• Dizziness or lightheadedness: Especially when standing up quickly.

It’s crucial to wait at least 14 days after stopping an SSRI before starting selegiline. The same applies in reverse. Mixing them can trigger serotonin syndrome - a potentially life-threatening condition marked by high fever, confusion, rapid heartbeat, and muscle rigidity.

How long does it take to work?

Unlike SSRIs, which often take 4-6 weeks to show effects, selegiline can start working faster - sometimes in under two weeks. Many patients report increased energy and improved focus before their sadness lifts. That’s because dopamine changes happen quicker than serotonin changes.

Full benefits usually appear by week 4-6. If there’s no improvement by then, it’s unlikely to work. Doctors typically give it a 6-8 week trial before deciding to switch.

Cost and availability

The brand-name patch, Emsam, is expensive in the U.S. - over $600 for a 30-day supply without insurance. In the UK, it’s available on the NHS but only after other options have failed. Generic selegiline tablets are much cheaper - often under £10 for a month’s supply.

But here’s the catch: generic tablets require strict diet control and carry higher risk. The patch is more convenient and safer, even if it costs more. Some patients split the patch to stretch their supply, but that’s not recommended without medical supervision.

Alternatives to consider

Selegiline isn’t the only option for treatment-resistant depression. Other MAOIs like phenelzine (Nardil) and tranylcypromine (Parnate) are more potent but come with stricter diets and more side effects. Esketamine (Spravato) nasal spray is newer and works fast, but it’s given in a clinic and costs over £1,000 per dose.

Non-drug options like transcranial magnetic stimulation (TMS) or ketamine infusions are also worth exploring. But they’re not always covered by insurance, and access is limited.

Selegiline stands out because it’s one of the few options that works on dopamine - a key player in motivation and energy - without requiring daily injections or clinic visits.

Final thoughts

Selegiline for depression isn’t a first-line fix. But for those who’ve tried everything else and still feel stuck, it can be a game-changer. It’s not magic. It doesn’t work for everyone. But for people with low energy, lack of motivation, or atypical depression, it offers something few other drugs do: a real return to life.

If you’ve been on antidepressants for years and still feel like you’re going through the motions, talk to your doctor about selegiline. It might be the missing piece.