Depression is one of the most common mental health conditions, and for many people, standard therapies like antidepressants and psychotherapy lead to lasting recovery.
But sometimes, these treatments don’t work as expected. Symptoms don’t improve, and relief remains out of reach…
This is known as treatment-resistant depression (TRD) – a form of depression that doesn’t respond to standard therapy or medication. But despite how it sounds, TRD is treatable – it just requires a slightly different approach.
From expert psychiatric care and psychotherapy to advanced new treatments like Spravato® (esketamine therapy), there are several effective options available to help you overcome TRD.
In this article, we’ll explain what TRD is, why it happens, and the treatments that can help you or someone you care about find lasting relief.
What is treatment-resistant depression?
Treatment-resistant depression is a form of major depressive disorder (MDD). It’s officially defined as depression that doesn’t improve after trying at least two antidepressant medications at adequate doses and durations (usually six to eight weeks each).
TRD can show up in a few different ways:
- Symptoms that don’t improve at all with antidepressants.
- Symptoms that only improve partially.
- Symptoms that return after a previous episode, and no longer respond to a treatment that worked in the past.
It’s important to clarify that treatment resistance has nothing to do with someone refusing or resisting help. The term describes depression that hasn’t responded to medical treatments – not a lack of effort or willpower.
TRD is simply another way depressive illness can show up, and about one in three people treated for major depression will face it at some point. Although the name might sound discouraging, there are treatments that can help – it’s just a case of needing a more tailored or advanced approach.
Why some depression is resistant to treatment
Depression is complex, and so is the way people respond to medication or therapy.
When symptoms don’t improve, it’s rarely due to one single cause. Some of the most common factors include:
- Biology & genetics: Some people’s brain chemistry systems (serotonin, norepinephrine, dopamine, glutamate) simply respond differently to standard medications.
- Co-occurring conditions: Anxiety disorders, PTSD, bipolar traits, substance use, chronic pain, or even thyroid issues can all impact treatment response.
- Stress or trauma: Ongoing stress can change how the brain’s stress-response systems function, which can make depression harder to treat.
- Metabolic or absorption issues: Some people metabolize medications differently, leading to lower effective concentrations in the brain.
- Treatment fit and timing: Sometimes the dosage, duration, or antidepressant class needs adjusting – or treatment just needs more time.
Because these factors often overlap, every case of depression requires an individual approach. But the important thing to remember is that depression treatment often requires adjustment, and there are always other options. As long as you continue to seek help, your psychiatric care team will be able to keep adjusting your treatment plan to find what will work for you.
Symptoms and diagnosis of treatment-resistant depression
Symptoms of TRD are the same as major depressive disorder – sadness, loss of interest, fatigue, sleep changes, and difficulty concentrating. However, with TRD, the symptoms linger despite treatment.
People with treatment-resistant depression are also more likely to experience:
- Longer-lasting depressive episodes
- More severe symptoms
- Higher recurrence of depressive episodes
- Deeper emotional flattening and reduced ability to feel pleasure (anhedonia)
- Heightened anxiety or agitation
- Suicidal thoughts or ideation
To be diagnosed with treatment-resistant depression, you’ll have to have tried at least two antidepressants without experiencing relief. However, diagnosis involves more than just counting failed medications.
To reach a diagnosis, a psychiatrist will:
- Review your full treatment history (which medications, what doses, and for how long).
- Evaluate whether the medications were taken consistently and tolerated well.
- Check for co-existing conditions or medical issues that can mimic or worsen depression.
- Consider whether a different diagnosis – such as bipolar depression – better fits your experience.
From there, they can identify whether your depression truly meets the definition of TRD, and what options are available next.
*If you suspect you have treatment-resistant depression, it’s important to seek help from someone who specializes in diagnosing and treating mental health conditions. If you started treatment with your primary care doctor and aren’t experiencing relief, it’s important to ask for a referral to a psychiatrist.
What to do if your depression is resistant to treatment
If you’ve been treated for depression and haven’t found relief, it doesn’t mean nothing will work. It just means it’s time to review your treatment plan and consider other approaches.
First-line treatments for depression
Depression treatment usually starts with one – or both – of the following:
- Antidepressant medication (often SSRIs or SNRIs, which have the best success rates and fewest side effects)
- Psychotherapy (talk therapy), such as cognitive behavioral therapy (CBT), interpersonal therapy (IPT), or dialectical behavior therapy (DBT)
These treatments are highly effective for many people, but they often need adjustments and fine-tuning – such as changing medications, tweaking dosage frequency, or combining approaches for a stronger effect. That’s why regular follow-ups with your psychiatric care team or therapist are so important.
Advanced treatments for treatment-resistant depression
If your symptoms persist despite these first-line therapies, a psychiatrist will guide you through next-step options. These might include:
- Medication adjustments or combinations – changing to a different class of antidepressant, or adding another medication such as an atypical antipsychotic or mood stabilizer to strengthen the antidepressant effect.
- New or alternative drug classes – such as esketamine therapy (Spravato®), a newer treatment that works through a different mechanism in the brain than traditional antidepressants.
- Brain stimulation therapies – such as repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT), which use magnetic pulses or gentle electrical stimulation to help reset mood-regulating pathways in the brain.
Each option has its benefits and considerations, but Spravato® (esketamine) represents one of the most significant breakthroughs in depression treatment in recent years, and is frequently now considered the best option for treating TRD.
Spravato is the only FDA-approved medication specifically for treatment-resistant depression. It works differently from traditional antidepressants by targeting the brain’s glutamate system – helping restore connections that regulate mood, and finally providing long-lasting relief. It’s a self-administered nasal spray, taken in a clinical setting under medical supervision, and many people start to experience relief within as little as 24 hours. While Spravato can have some side effects, they are generally short lived and it is a well-tolerated medication with remarkable results.
At REACH Behavioral Health, we’re proud to offer Spravato esketamine therapy at our Westpark clinic in Cleveland, where patients receive compassionate, closely monitored care in a calm and supportive environment.
Learn more about Spravato and what it involves here.
How we approach treatment-resistant depression at REACH Ohio
Depression is rarely treated through one single method. The best outcomes almost always come from a holistic, individualized approach that combines several forms of care.
That’s why at REACH Ohio, we offer therapy, psychiatric care and medication management, and Spravato® (esketamine) – the three treatment paths proven to most effectively help people recover from depression and build lasting stability – all under the one roof:
- Expert psychiatric care: Comprehensive evaluation, diagnosis, medication management, and ongoing monitoring.
- Psychotherapy: Evidence-based therapies such as CBT, DBT, and trauma-focused care, tailored to your individual needs.
- Spravato® esketamine therapy: Available at our Westpark (Cleveland’s West Side) clinic for adults with treatment-resistant depression.
- Collaborative care: Our psychiatrists, therapists, and nurse practitioners work together to ensure every part of your mental health is addressed.
By combining these services within one integrated care team, we make treatment simpler, safer, and more effective. While medication can bring relief and stability, therapy helps strengthen the changes that last. At REACH, you don’t have to figure it out alone – we’ll help you find the combination of care that truly works for you.
Find relief with depression specialists at REACH Ohio
If you’ve been living with depression that just won’t lift, it’s time to take the next step.
With compassionate depression specialists and multiple treatment options, REACH Behavioral Health is here and committed to helping you find a treatment plan that will work.
You don’t have to face depression alone, and treatment-resistant depression can be treated. Reach out today and take the first step toward feeling better.
Quick-answer FAQs about treatment-resistant depression
What is treatment-resistant depression (TRD)?
TRD is depression that doesn’t improve after trying at least two antidepressants at an adequate dose and duration.
How is treatment-resistant depression diagnosed?
Treatment-resistant depression is diagnosed by reviewing treatment history, ruling out other conditions, and assessing symptom persistence despite treatment efforts.
Does TRD mean my depression can’t be treated?
Not at all. Treatment-resistant depression simply means standard/first-line depression treatments haven’t worked yet – but there are still other approaches available.
What are the best treatments for treatment-resistant depression?
Esketamine (Spravato®) is one of the most effective treatments available today, and is increasingly considered to be the best option for treating TRD.
Where can I access Spravato (esketamine therapy) in Ohio?
At REACH Behavioral Health, we offer Spravato esketamine therapy at our Westpark location (on the West Side of Cleveland), under expert medical supervision.
What is the usual Spravato TRD dosing frequency?
The Spravato treatment plan – or dosing frequency – is always tailored to each individual. However, most patients begin with two sessions a week for the first month, followed by once-weekly or biweekly sessions as symptoms improve.