Roughly one in three people diagnosed with major depressive disorder does not respond adequately to standard antidepressant treatment — a clinical pattern that has a name, a definition, and a growing range of evidence-based options. At Tri-Cities Infusion & Wellness Clinic, we work with patients in Kennewick, Richland, Pasco, and the surrounding area who have been through the standard medications and are still struggling. Understanding what treatment-resistant depression actually means is the first step toward knowing what comes next.
What “Treatment-Resistant” Actually Means
The term treatment-resistant depression — often abbreviated as TRD — has a specific clinical definition that is worth understanding precisely, because it is frequently misapplied. TRD is generally defined as a major depressive episode that has not responded adequately to at least two antidepressant medications taken at therapeutic doses for a sufficient duration, typically six to eight weeks each (Abdallah et al., 2019). That distinction matters. A patient who tried one medication at a low dose for three weeks and stopped due to side effects may not meet the clinical threshold for TRD — but a patient who has completed two or more full trials without meaningful improvement almost certainly does.
This precision is important because TRD is not a character flaw, a sign of weakness, or evidence that depression is permanent. It is a clinical signal — a pattern in the data of someone’s treatment history — that points toward a different neurobiological picture than the one standard medications are designed to address.
Several factors can contribute to why some depression resists standard treatments. Genetic variations in how individuals metabolize medications can render standard doses ineffective before they have a chance to work. Underlying conditions like thyroid dysfunction, chronic inflammation, or sleep disorders can independently sustain depressive symptoms. And for some patients, the neurobiology of their depression involves systems that SSRIs and SNRIs — the two most commonly prescribed antidepressant classes — simply do not target directly.
The Glutamate System and Why It Changes the Picture
Most first-line antidepressants work by increasing the availability of serotonin, norepinephrine, or both in the brain’s synaptic spaces. These are the monoamine systems, and targeting them helps a significant number of people. But depression is not a single-pathway condition, and the monoamine hypothesis does not account for every presentation.
Research over the past two decades has increasingly pointed to the glutamate system — the brain’s primary excitatory neurotransmitter network — as a key factor in cases where serotonin-targeted treatment falls short (Bhatt et al., 2021). The NMDA receptor, a specific type of glutamate receptor, plays a central role in synaptic plasticity — the brain’s ability to strengthen and reorganize connections between neurons. When this system is dysregulated, it may contribute to the pattern of depression that does not respond to monoamine-targeting medications.
The National Institute of Mental Health has highlighted new research supporting ketamine — which works through NMDA receptor blockade in the glutamate system — as a rapid-acting treatment for depression, offering clinical evidence for patients who have not responded to standard care (NIMH, 2024). This research matters because it provides a neurobiological explanation for why a different mechanism can succeed where serotonin-targeting medications have not. For a plain-language overview of how ketamine works and what the evidence says, see our Ketamine Facts page.
Ketamine Infusion Therapy as a Next Step
At Tri-Cities Infusion & Wellness Clinic, ketamine infusion therapy for depression is administered intravenously by Tyler Thornock and Ben Clark — both certified registered nurse anesthetists (CRNAs) with extensive experience in anesthesia and patient monitoring. The clinical oversight that comes with CRNA-administered infusions is not a minor detail; ketamine requires precise dosing and real-time response to how a patient is tolerating the infusion, and our team’s background is specifically suited to that task.
Before any infusion, we conduct a thorough health sync with each patient: a review of their full treatment history, a brief physical exam, and a direct conversation about whether ketamine is clinically appropriate for their situation. Patients who have been through multiple antidepressant trials often arrive with a complex history and a reasonable amount of skepticism, and we take both seriously. We do not default to any single protocol, and we do not proceed without a clear picture of what a patient has already tried and how they responded.
It is also worth noting what ketamine is not. It is not the same as SPRAVATO® — the esketamine nasal spray that received FDA approval specifically for treatment-resistant depression. SPRAVATO® is a distinct formulation, available only through certified healthcare settings. Intravenous ketamine and SPRAVATO® share a related mechanism but differ in administration, formulation, and regulatory status. We offer IV ketamine infusion therapy; we do not currently offer SPRAVATO®. If you are uncertain which option may be right for you, that is exactly the kind of question to bring to a consultation.
What to Expect From the Process
Once a patient completes the pre-treatment evaluation and is cleared for ketamine infusion, our team prepares them for the session in one of our private infusion rooms. Each room is designed to be comfortable — recliners, a calm environment, and the option to rest, watch a movie, or simply be still during the infusion. Our staff is present throughout and monitors patients through recovery before discharge.
Clinical evidence supports both single and repeated ketamine infusions for treatment-resistant depression, with research showing that multiple sessions can produce cumulative antidepressant benefits and extend remission periods (Abdallah et al., 2019). We discuss the expected structure of a treatment course — including how many sessions we typically recommend and what monitoring looks like over time — during the initial consultation, before any commitment is made. Our blog post on understanding ketamine treatment for depression in Kennewick, WA offers additional context on what patients can expect from this process.
Barriers We Hear About Most
Insurance uncertainty. Coverage for ketamine infusion therapy varies by plan and is not universal. We accept Asuris, Providence Health Plan, Cigna, Premera, LifeWise, and First Choice Health, and we encourage patients to contact us to check on their specific coverage before assuming the worst. We are not in-network with Medicare or Medicaid for infusion services; patients on those plans can request documentation and invoices from our team to submit to their insurer for potential direct reimbursement. Our team will walk through the financial side of any treatment before a patient commits to anything — that transparency is part of how we operate.
Skepticism after repeated treatment failures. This is one of the most common things we encounter, and we think it is a reasonable response to a difficult experience. Patients who have been through multiple antidepressant trials — and perhaps other interventions as well — often arrive with genuine exhaustion alongside their questions. Our approach is to address that skepticism directly: explain the mechanism, review the evidence, and give an honest assessment of whether ketamine is likely to be a good fit for a given patient’s history. We do not guarantee outcomes. No ethical provider can. We encourage anyone considering ketamine to discuss the full picture with their current provider as well — the goal is a decision that is right for your situation, not simply a path forward with us.
Frequently Asked Questions
How do I know if I qualify as treatment-resistant? The clinical threshold is generally two or more antidepressant medication trials at therapeutic doses for adequate duration without sufficient response. If you are unsure whether your prior trials meet that standard, the pre-treatment consultation process will clarify that. Some patients who believe they meet the criteria have not actually completed a full therapeutic trial; others have a clear pattern of non-response. Both answers are useful.
Is ketamine infusion the same as SPRAVATO®? No. SPRAVATO® is an FDA-approved esketamine nasal spray administered only in certified clinical settings and approved specifically for treatment-resistant depression. IV ketamine and SPRAVATO® work through a related but distinct mechanism, are formulated differently, and have different regulatory histories. We offer IV ketamine at our clinic; patients with questions about the differences between the two options are encouraged to raise them during a consultation.
How fast does ketamine work for depression? One of the characteristics that distinguishes ketamine from standard antidepressants is the speed of response. Many patients report noticing changes within hours to days of their first infusion rather than waiting the weeks associated with SSRIs or SNRIs. That said, individual response varies, and a single infusion is typically not the complete picture — most patients undergo a series of sessions.
Will I need to stay on my antidepressants if I try ketamine? That decision is made on an individual basis during the pre-treatment evaluation and ongoing monitoring. Some patients continue existing medications alongside ketamine infusion therapy; others adjust their regimen under medical guidance. We do not apply blanket rules — the decision is shaped by your history, your response to treatment, and your goals.
Key Takeaways
- Treatment-resistant depression (TRD) is a clinical designation for major depression that has not responded adequately to at least two antidepressant trials at therapeutic doses — it is a pattern in the data, not a verdict on what is possible.
- Standard antidepressants target monoamine systems (serotonin, norepinephrine); TRD often involves the glutamate system — specifically NMDA receptors — which those medications do not directly address.
- Ketamine infusion therapy works through NMDA receptor blockade and has demonstrated rapid antidepressant effects in patients who have not responded to multiple prior treatments.
- SPRAVATO® (the esketamine nasal spray) is a distinct FDA-approved formulation; we offer IV ketamine infusion, not SPRAVATO®, and the two are not interchangeable.
- Our CRNA-led team in Kennewick conducts a thorough pre-treatment evaluation before any infusion to determine whether ketamine is clinically appropriate for each patient; results vary by individual.
If your depression has not responded to antidepressants, that history is information — not a permanent ceiling. We invite you to schedule a consultation with our team at Tri-Cities Infusion & Wellness Clinic in Kennewick, Washington, and have a direct conversation about what your treatment history tells us and what options may be worth exploring next. Call us at 509-383-8760 or request a consultation at tricitieswellness.com/contact-us. We will be honest with you about what to expect.
References
Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2019). Ketamine and rapid-acting antidepressants: A window into a new neurobiology for mood disorder therapeutics. Annual Review of Medicine, 70, 319–330. https://pmc.ncbi.nlm.nih.gov/articles/PMC5148235/
Bhatt, S., Bhatt, D., Bhatt, J., & Bhatt, P. (2021). NMDA receptors and ketamine’s antidepressant mechanism. Translational Psychiatry. https://pmc.ncbi.nlm.nih.gov/articles/PMC5148235/
National Institute of Mental Health. (2024). New hope for rapid-acting depression treatment. https://www.nimh.nih.gov/news/science-updates/2024/new-hope-for-rapid-acting-depression-treatment
Medical Disclaimer
The information in this blog is for educational purposes only and does not constitute medical advice. Ketamine infusion therapy for treatment-resistant depression should only be pursued under the supervision of a licensed healthcare provider familiar with your full medical and psychiatric history. Individual results vary — outcomes are not guaranteed, and what is appropriate for one patient may not be appropriate for another. This content is not a substitute for a professional evaluation. If you are experiencing a mental health crisis or thoughts of self-harm, please call or text 988 to reach the Suicide and Crisis Lifeline or go to your nearest emergency room.
