What Is Treatment-Resistant Depression?
Treatment-resistant depression (TRD) is defined as depression that has not responded adequately to at least two different antidepressant treatments taken at appropriate doses and for an appropriate duration. As a result, it is one of the most common yet underdiagnosed conditions in psychiatry.
In fact, TRD is not a character flaw, and it is not a sign that someone is beyond help or has not tried hard enough. Rather, it is a neurological reality that requires a more targeted clinical approach than standard antidepressant therapy can provide.
Research published in Frontiers in Psychiatry (2025) estimates TRD prevalence at 30 to 40 percent of patients treated with antidepressants, making it far more common than most people, and many clinicians, realize.
Source: Frontiers in Psychiatry, 2025
If antidepressants have stopped working, never worked, or stopped working after a period of improvement, that is not the end of the road. It is a clinical signal that a different approach is needed.
Signs You May Have Treatment-Resistant Depression
Many people with TRD have been struggling for years without a clear name for what they are experiencing. They have tried medications, and while some worked partially, others stopped working over time or never produced meaningful relief at all.
You may be experiencing treatment-resistant depression if you:
- Have tried two or more antidepressants without significant improvement
- Felt better initially on a medication, but noticed symptoms returning over time
- Continue to experience depression despite being consistent with treatment
- Have cycled through multiple medications with diminishing results
- Experience side effects that make it difficult to stay on your prescribed medication
- Feel emotionally flat or numb rather than genuinely improved
- Struggle to function at work, in relationships, or in daily life despite being on medication
- Have a history of trauma, chronic stress, or co-occurring conditions like PTSD or ADHD
If any of these resonate, a comprehensive psychiatric evaluation at our TRD Clinic is an important next step. Read more about why antidepressants stop working.
Who the TRD Clinic Is For, and When Something Else Comes First
The TRD Clinic is built for adults whose depression has not responded to at least two adequate antidepressant trials, including patients with bipolar depression, depression complicated by PTSD, OCD or ADHD, and patients whose referring therapist or physician has run out of medication options. You do not need a formal TRD diagnosis to be evaluated. If you suspect you fit, that is enough to book.
A few situations call for a different first step. Active psychosis or mania needs stabilization before interventional treatment. An untreated substance use disorder is addressed first or alongside, because it changes which treatments are safe. And if you are in crisis right now, call or text 988 or go to the nearest emergency department. Our evaluation is the right next step once you are safe. If you are worried about someone else, read our guide on how to help someone who is suicidal.
Why Antidepressants Stop Working
Most traditional antidepressants work by targeting the serotonin system in the brain. For many patients, this approach produces meaningful improvement. However, depression is not a single, uniform condition, and serotonin is only one of several systems involved.
Additionally, research increasingly shows that other brain systems, including the glutamate system and specific neural circuits involved in mood regulation, play a significant role in depression, especially in cases that do not respond to serotonin-based medications. As a result, patients whose depression is rooted in these other systems may find that traditional antidepressants have a ceiling on what they can accomplish. Social feedback can also shape depression in ways medication does not address, as a recent study on social media likes and depression shows.
The Role of Chronic Stress in Treatment Resistance
Beyond brain chemistry, chronic stress is one of the most significant and underrecognized drivers of treatment resistance. When stress becomes chronic, it physically changes the structure of the brain in ways that make depression harder to treat with standard antidepressants.
A 2025 study published in the International Journal of Molecular Sciences found that prolonged HPA axis activation disrupts cortisol regulation and leads to neurobiological changes in the hippocampus that are directly linked to the development and persistence of depressive disorders that do not respond to standard treatment.
Furthermore, neuroinflammation driven by chronic stress affects up to 27 percent of patients with major depressive disorder and is associated with a more severe, treatment-resistant trajectory. Because of this, standard antidepressants, which do not directly address inflammatory pathways, are less effective for this population. Learn more about the link between chronic stress and treatment-resistant depression.
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Advanced Treatment Options at GBH's TRD Clinic
Treatment-resistant depression is highly treatable with the right approach. In fact, at Georgia Behavioral Health, we offer advanced treatment options that work through entirely different mechanisms than traditional antidepressants, designed specifically for patients who have not found relief through medication alone.
TMS Therapy
FDA-cleared, non-invasive brain stimulation that uses magnetic pulses to target and reset mood-regulating circuits. No sedation required. Patients return to daily activities immediately.
Learn about TMS TherapySPRAVATO (Esketamine)
FDA-approved nasal spray targeting the glutamate system for rapid relief of TRD symptoms. Can produce measurable improvement in some patients within hours of the first session.
Learn about SPRAVATOIV Ketamine Therapy
Fast-acting infusion treatment targeting the brain's glutamate system, used off-label for patients who have not responded to traditional medications.
Learn about IV KetaminePsychiatric Care
Comprehensive evaluations and medication management that look beyond a single diagnosis to understand the full clinical picture, including co-occurring conditions.
Learn about Psychiatric CareEMDR Therapy
For patients where trauma or adverse experiences are driving or compounding depression, EMDR addresses root psychological drivers that medication alone cannot reach.
Learn about EMDRTalk Therapy
Evidence-based psychotherapy used alongside medical treatment to address stress patterns, cognitive responses, and nervous system regulation for more durable outcomes.
Learn about Talk TherapyTMS vs. SPRAVATO vs. IV Ketamine at a Glance
All three interventional treatments are offered here, and many patients are candidates for more than one. The right choice depends on your history, your insurance, how quickly you need relief, and whether you can arrange a ride home on treatment days.
| TMS Therapy | SPRAVATO (esketamine) | IV Ketamine | |
|---|---|---|---|
| FDA status | FDA-cleared for depression, OCD, anxious depression | FDA-approved for treatment-resistant depression | FDA-approved anesthetic, used off-label for depression |
| How it is given | Magnetic coil on the scalp | Nasal spray under supervision | Intravenous infusion |
| Visit length | 20 to 40 minutes | About 2.5 hours including observation | About 2 hours including infusion and monitoring |
| Course | 5 days a week for about 6 weeks | Twice weekly for 4 weeks, then weekly, then every 1 to 2 weeks | Typically 6 infusions over 2 to 3 weeks, then as needed |
| Sedation or dissociation | None. You drive yourself. | Likely. No driving that day. | Common. No driving that day. |
| Insurance | Usually covered | Usually covered with prior authorization | Not typically covered |
| Speed of response | Gradual, usually weeks 3 to 4 | Hours to days | Hours to days |
Not sure which treatment is right for you? Read our comparison of TMS therapy vs SPRAVATO to understand the differences, or schedule a comprehensive evaluation and we will help you find the right path forward.
What to Expect at the TRD Clinic
Screening Call
A brief conversation with our team, by phone or online, to review your treatment history and confirm the TRD Clinic is the right fit. Bring a list of medications you have tried, with rough doses and durations if you have them.
Comprehensive Psychiatric Evaluation
About an hour with a licensed psychiatric provider. We look beyond depression alone at trauma history, ADHD, bipolar spectrum, anxiety, sleep, chronic stress and medical contributors, because a missed co-occurring condition is one of the most common reasons treatment stalls.
A Treatment Recommendation You Can Understand
We walk through the options that fit you, including TMS, SPRAVATO, IV ketamine, medication changes and therapy, and explain the why behind each. We also tell you up front what your insurance is likely to cover and handle prior authorization.
Treatment
Interventional treatments are delivered in our Norcross office by our own team, with symptom tracking at regular intervals so you and your provider can see what is changing.
Follow-Up and Co-Management
You keep your existing therapist or prescriber if you have one. We send progress updates to referring clinicians and plan maintenance or next steps together once the initial course is complete.
You Have Not Run Out of Options
If antidepressants have not worked for you, that is a clinical signal, not a life sentence. Our TRD Clinic serves patients across Atlanta, Norcross, Johns Creek, Duluth, and Gwinnett County.
Book a Consultation
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Co-Occurring Conditions That Complicate Treatment
Depression rarely exists in isolation. In fact, co-occurring conditions can significantly affect treatment response and are an important part of any comprehensive TRD evaluation. When these conditions go unidentified, patients may cycle through medications without ever addressing the full clinical picture.
Conditions commonly seen alongside TRD include:
- PTSD: Antidepressants may address some depressive symptoms while leaving underlying trauma unresolved
- ADHD: Mood dysregulation related to ADHD can mimic or worsen depression and may not respond to standard antidepressant therapy
- Generalized Anxiety Disorder: Complicates the clinical picture and affects which treatments are most appropriate
- Bipolar Disorder: Sometimes misdiagnosed as major depressive disorder, leading to treatments not matched to the actual condition
- Chronic pain or inflammatory conditions: Emerging research connects systemic inflammation to depression that does not respond to serotonin-based treatment
Because of this, a comprehensive psychiatric evaluation that looks beyond depression alone is essential to understanding why treatment may not be working and what approach is most likely to help.
Why Choose the GBH TRD Clinic in Norcross
- Psychiatrist-led. Every patient is evaluated and followed by a board-certified psychiatrist. Dr. Neha Khurana, MD is an Atlanta Magazine Top Doctor for General Psychiatry in 2025 and 2026.
- All three interventional treatments under one roof. TMS, SPRAVATO and IV ketamine are all offered here, so the recommendation is based on what fits you, not on the one tool a clinic happens to have.
- Whole-picture evaluation. We screen for ADHD, bipolar spectrum, trauma and anxiety as part of every TRD workup, because the missed diagnosis is often the reason nothing has worked.
- Insurance handled for you. We verify benefits and manage prior authorization for TMS and SPRAVATO, and tell you plainly when a treatment is not covered.
- Co-management with your existing care team. Referring therapists and physicians receive progress updates throughout treatment.
- Convenient location. 4720 Peachtree Industrial Blvd, Suite 4101 in Norcross, minutes from Peachtree Corners, Duluth, Johns Creek and Suwanee, with parking on site.
- Care in English, Korean and Spanish. 한국어 진료 가능합니다. Se habla español.
TRD Resources and Research
From the GBH Blog
→ What Is Treatment-Resistant Depression? Answers to the Questions Patients Are Actually Asking → Why Antidepressants Stop Working → TMS Therapy vs SPRAVATO: Which Is Right for You? → Men's Mental Health and Treatment-Resistant Depression → The Link Between Chronic Stress and Treatment-Resistant Depression → Social Media Likes and Depression: What a New JAMA Psychiatry Study Actually Found → How to Help Someone Who Is Suicidal: What to Say and What to DoAre You a Clinician or Therapist?
Download our TRD Clinic Referral Guide for information on referring patients to our practice. We serve Atlanta, Norcross, Johns Creek, Duluth, and the greater Gwinnett County area.