When Nothing Works: What to Know About Treatment-Resistant Depression

What Is Treatment-Resistant Depression?

For many people, depression is a condition that eventually improves with the right combination of therapy, support, and medication. But for others, the road is more difficult. If you’ve tried multiple antidepressants with little or no relief, you may be living with treatment-resistant depression (TRD).

TRD isn’t a formal diagnosis you’ll find in a chart — it’s a term used when depression continues despite trying at least two to four different antidepressant treatments at adequate doses and durations. And it’s more common than most people think.

Why TRD Happens

Depression is complex. It doesn’t come from one cause, and it doesn’t respond to just one kind of treatment. For some people, traditional antidepressants — which typically work by altering serotonin or norepinephrine levels — may not be enough.

Some possible reasons why depression persists include:

• Biological differences in how the brain responds to treatment

• Chronic stress or trauma that hasn’t been fully processed

• Underlying inflammation or other health conditions

• Genetic factors that affect how medications are metabolized

• Mismatch in medication and brain chemistry

When relief doesn’t come, it can be frustrating, exhausting, and even isolating.

What Living With TRD Can Feel Like

If you’re experiencing TRD, you might recognize these feelings:

• You’ve tried more than two medications — and maybe even therapy — but nothing helps

• You feel emotionally flat, numb, or stuck

• It’s hard to imagine a future where you feel better

• You dread trying “just one more med” that might not work

• Your symptoms interfere with relationships, work, or motivation

These experiences are valid. Many people with TRD report feeling misunderstood or left behind — not because they aren’t trying, but because what’s available simply hasn’t worked for them.

Why Research Matters

Researchers and clinicians recognize that existing treatments aren’t always enough. That’s why studies are being conducted to explore new types of care, including innovative therapies that work differently from traditional antidepressants.

One area of exploration is psilocybin, the active compound found in certain psychedelic mushrooms. When paired with professional psychological support, it’s being studied for its potential to help people living with TRD in a controlled clinical setting.

This isn’t about casual use or recreational experiences — it’s about carefully monitored research looking at how one or two guided sessions could lead to measurable improvements in depression symptoms.

A Clinical Study Is Now Enrolling

Segal Trials is participating in a Phase III clinical research study evaluating COMP360, a synthetic form of psilocybin combined with professional support, for adults with treatment-resistant depression.

You may be eligible if you:

• Are 18 or older

• Have moderate to severe depression

• Have tried at least 2 antidepressants during your current episode without improvement

• Are willing to pause current depression treatments temporarily (under supervision)

• Have no history of psychosis, bipolar disorder, or recent substance use disorder

Learn more or see if you may qualify at 👉 SegalTrials.com