Treatment-resistant depression is not a personal failure or proof that recovery is impossible. It is a clinical term used when major depressive disorder has not improved adequately after appropriate antidepressant treatment.
For many patients, reaching this point follows months or years of medication changes, side effects, psychotherapy, and partial or short-lived improvement. Each unsuccessful treatment can make the next option feel less promising.
Research confirms that this experience is not rare. In the National Institute of Mental Health’s STAR*D study, approximately one-third of participants reached remission after the first medication step. Additional treatment steps helped some participants, but the likelihood of remission generally decreased as more strategies were needed.
For patients in Gallatin and across Sumner County, persistent depression should lead to a careful reassessment—not an assumption that nothing remains to try. At Three Rivers Wellness, we evaluate qualifying adults who want to understand whether IV ketamine or SPRAVATO® may fit into their broader depression treatment plan.
What Treatment-Resistant Depression Means
Treatment-resistant depression, or TRD, is commonly defined as major depressive disorder that has not responded adequately to at least two antidepressant trials completed at appropriate doses, durations, and levels of adherence.
There is no single definition used in every study or clinical setting. Some definitions require medications from different classes, while others focus on two adequate treatment failures regardless of class. The term also does not necessarily mean that a medication produced no benefit at all. A person may still meet criteria when treatment led to only partial improvement and significant symptoms remain.
TRD is a clinical description rather than a separate type of depression with one confirmed biological cause. Before applying the term, a provider should review questions such as:
- Was the diagnosis accurate?
- Was each medication taken consistently?
- Was the dose clinically appropriate?
- Did the trial last long enough?
- Did side effects prevent adequate treatment?
- Is another medical or psychiatric condition contributing?
- Could bipolar disorder, substance use, trauma, chronic pain, or a sleep disorder be affecting symptoms?
- Was psychotherapy available and appropriate for the patient’s needs?
This process helps distinguish true treatment resistance from situations in which treatment was incomplete, poorly tolerated, or directed at the wrong diagnosis.
Our overview of depression treatment in Gallatin explains the symptoms and treatment history we consider during an evaluation.
Why Antidepressant Medication May Fall Short
Depression is complex. Genetics, life experiences, stress, physical health, sleep, inflammation, hormones, substance use, and communication across multiple brain systems may all play a role.
Traditional antidepressants influence signaling involving serotonin, norepinephrine, dopamine, or a combination of these systems. They can be highly effective, but no medication works equally well for every person.
An inadequate response does not prove that one particular chemical imbalance is causing the depression. It also does not mean that medications affecting serotonin or norepinephrine were inappropriate. Instead, it may indicate that the diagnosis, treatment strategy, or biological response is more complicated than one medication can address.
Depending on the patient, established next steps may include:
- Adjusting the current medication
- Switching to another antidepressant
- Adding another medication
- Starting or revising psychotherapy
- Treating a co-occurring medical or psychiatric condition
- Addressing sleep, substance use, or medication adherence
- Evaluating a specialized treatment
Patients should not stop or change antidepressant medication without consulting the provider responsible for prescribing it. Abrupt changes may cause withdrawal symptoms, worsening depression, or other complications.
How IV Ketamine Differs From Conventional Antidepressants
Ketamine affects several biological systems, but one of its best-known actions involves N-methyl-D-aspartate, or NMDA, receptors within the glutamate system.
Glutamate is the brain’s primary excitatory neurotransmitter and participates in neural communication, learning, memory, and processes related to synaptic plasticity. Researchers believe ketamine’s antidepressant effects involve changes in communication across neural networks, although the full mechanism in humans remains under investigation.
This differs from the primary mechanisms associated with most conventional antidepressants. The distinction is scientifically important, but it should not be simplified into a claim that ketamine corrects the “real” cause of treatment-resistant depression.
There is currently no routine clinical test that can show whether someone’s depression results from glutamate dysregulation or predict whether that person will respond to ketamine. If you’re curious about what the experience involves, our article on what ketamine therapy feels like offers a patient-focused overview.
What the Research Shows About IV Ketamine
Randomized clinical trials have found that a single IV ketamine infusion can reduce depression symptoms more rapidly than a comparison treatment in some adults with treatment-resistant depression. Changes have been detected within hours or by the following day in some studies.
That rapid onset is one reason IV ketamine has become an important area of depression research. However, several qualifications matter:
- Not every patient responds.
- Improvement after one infusion may be temporary.
- A rapid response does not guarantee remission.
- Repeated infusions may be needed to evaluate benefit.
- The ideal maintenance schedule has not been established.
- Long-term safety and durability require continued study.
- Research outcomes do not predict one individual’s experience.
IV ketamine has a meaningful evidence base for treatment-resistant depression, but it should not be described as universally effective, permanent, or risk-free. Our article on IV ketamine for treatment-resistant depression provides more context about the research and the clinic’s approach.
Understanding the Off-Label Status of IV Ketamine
Three Rivers Wellness offers IV ketamine infusions for qualifying patients with treatment-resistant depression.
This psychiatric use is off-label. That means the specific IV protocol for depression is not included in ketamine’s FDA-approved labeling.
Off-label prescribing is used in many areas of medicine, but the term does not guarantee that a treatment is safe, effective, or appropriate for a particular patient. It means the provider must use careful clinical judgment and explain:
- The available evidence
- Important research limitations
- Potential benefits and risks
- Reasonable alternatives
- Financial considerations
- The possibility of partial, temporary, or no improvement
Treatment should begin only after an individualized evaluation and informed discussion.
What SPRAVATO® Is
SPRAVATO® is the brand name for esketamine nasal spray. Esketamine is related to ketamine, but SPRAVATO® and IV ketamine are distinct treatments.
SPRAVATO® is FDA-approved for treatment-resistant depression in adults. Under its current prescribing information, it may be used by itself or together with an oral antidepressant for TRD.
It is also approved together with an oral antidepressant for depressive symptoms in adults with major depressive disorder accompanied by acute suicidal ideation or behavior. Its effectiveness in preventing suicide or reducing suicidal thoughts or behavior has not been established, and it does not replace hospitalization when a higher level of care is clinically necessary.
SPRAVATO® is self-administered by the patient under healthcare-provider supervision in a certified treatment setting. It cannot be taken home. Patients are monitored for at least two hours because of risks that include:
- Sedation
- Dissociation
- Respiratory depression
- Increased blood pressure
- Impaired attention and judgment
- Abuse and misuse
Three Rivers Wellness is a certified provider offering SPRAVATO® treatment in Gallatin for patients who meet clinical criteria.
IV Ketamine and SPRAVATO® Are Not Interchangeable
Both treatments affect NMDA-receptor and glutamate signaling, but important differences remain.
IV ketamine contains two molecular forms of ketamine and is delivered directly into a vein. SPRAVATO® contains esketamine and is administered through a nasal device.
They also differ in:
- FDA regulatory status
- Treatment schedule
- Administration process
- Monitoring requirements
- Available clinical evidence
- Potential insurance coverage
- Cost and prior-authorization pathways
- Individual medical considerations
One treatment should not be assumed to be stronger, safer, or more appropriate for every patient. The choice depends on diagnosis, prior treatment history, medical risks, patient preferences, treatment access, and financial considerations.
Our comparison of SPRAVATO® and IV ketamine explains these differences in greater detail.
What Three Rivers Wellness Offers Gallatin Patients
Three Rivers Wellness provides outpatient evaluation and monitored treatment for qualifying adults interested in IV ketamine or SPRAVATO®.
Our evaluation includes a review of:
- Current depression symptoms
- Previous diagnoses
- Antidepressant trials
- Psychotherapy history
- Current medications and supplements
- Medical conditions
- Cardiovascular risks
- Substance-use history
- Previous treatment side effects
- Safety concerns and treatment goals
A consultation does not obligate a patient to begin treatment. Its purpose is to determine whether further evaluation is appropriate, identify potential risks, and provide realistic expectations.
No psychiatric referral is required to request a consultation, although documentation of previous treatment can help our team evaluate whether TRD criteria have been met. We also encourage coordination with the patient’s existing psychiatrist, therapist, primary-care provider, or other members of the treatment team.
What Happens During an IV Ketamine Infusion?
Our mental-health infusions generally last approximately 40 to 60 minutes, with additional time needed for preparation and recovery.
Patients remain in an outpatient clinical environment where their response and relevant vital signs can be monitored. Possible effects during or shortly after an infusion include:
- Dissociation or a sense of detachment
- Changes in visual, auditory, or time perception
- Dizziness or lightheadedness
- Nausea
- Sleepiness
- Anxiety or emotional discomfort
- Temporary increases in blood pressure or heart rate
- Impaired judgment or coordination
The experience varies. Some patients tolerate perceptual changes well, while others find them uncomfortable. These effects should not be described as universally pleasant, minor, or proof that treatment is working.
Patients need to arrange transportation and follow all post-treatment restrictions. They should not plan to drive themselves home. For more detail on what to expect, see our overview of common ketamine therapy reactions.
Our Initial IV Ketamine Protocol
Our standard mental-health protocol begins with six IV ketamine infusions administered over approximately two to three weeks.
This schedule is the clinic’s starting framework. It is not an FDA-approved depression protocol or a guarantee that every patient will improve within six sessions.
We assess response throughout the initial series by reviewing:
- Changes in depression symptoms
- Daily functioning
- Motivation and engagement
- Sleep and activity
- Side effects and tolerability
- The degree and duration of any improvement
- Whether continued treatment remains clinically justified
Some patients notice improvement early in the series. Others experience gradual changes, and some do not improve enough to continue.
When a patient has a meaningful response, additional infusions may be considered individually. Research has not established one ideal maintenance schedule, and patients should not be promised permanent remission or a fixed period of relief.
Our article about maintaining depression improvement after an initial ketamine series explains why follow-up decisions depend on the individual response.
What a SPRAVATO® Treatment Schedule May Involve
SPRAVATO® treatment for TRD generally begins with an induction period involving twice-weekly appointments for four weeks. Treatment frequency is then reduced and individualized according to response and tolerability.
Each session includes administration in the clinic followed by at least two hours of observation. Patients must arrange transportation and should not drive or operate machinery until the next day after a restful sleep.
The treatment schedule and dose may be adjusted based on:
- Symptom response
- Side effects
- Blood-pressure changes
- Sedation or dissociation
- Overall tolerability
- Whether continued treatment provides sufficient benefit
Patients should not assume that SPRAVATO® will require the same schedule as IV ketamine or that response to one predicts response to the other. Our guide on Spravato patient requirements in Tennessee outlines the eligibility criteria in detail.
Cost and Insurance Considerations
IV ketamine for depression is commonly self-pay because its psychiatric use is off-label and many insurance plans do not cover it.
SPRAVATO® may be covered by some insurance plans for qualifying patients because it has FDA-approved depressive indications. Coverage is not automatic. Insurers may require:
- Documentation of previous antidepressant treatment
- Prior authorization
- A qualifying diagnosis
- Copayments or deductibles
- Treatment at a certified center
- Ongoing evidence that treatment remains medically necessary
Three Rivers Wellness can help patients understand the administrative process, but the insurance company makes the final coverage decision. Pricing, benefits, and financial responsibility should be confirmed before treatment begins.
Frequently Asked Questions
How Is Treatment-Resistant Depression Officially Defined?
TRD is commonly defined as major depressive disorder that has not responded adequately to at least two antidepressant trials completed at appropriate doses and durations. Definitions vary, and medication count alone is not enough. Diagnosis, adherence, side effects, co-occurring conditions, and the adequacy of each trial should also be reviewed.
Does Having TRD Mean Antidepressants Will Never Help Me?
No. Treatment resistance describes what has happened so far; it does not predict that every medication or future treatment will fail. Some patients benefit from medication changes, combination treatment, psychotherapy, specialized interventions, or treatment of a previously unrecognized condition.
How Quickly Can IV Ketamine Work?
Clinical studies have detected symptom improvement within hours or by the following day in some patients. Others improve more gradually or do not experience a meaningful response. “Rapid-acting” does not mean immediate, guaranteed, or permanent.
How Quickly Can SPRAVATO® Work?
Some patients experience improvement during the four-week induction phase, and clinical studies have also examined symptom changes beginning within the first day. Individual timelines vary. The need for continued treatment is assessed according to response and tolerability rather than a promised onset.
Does Insurance Cover IV Ketamine or SPRAVATO®?
IV ketamine is commonly self-pay because its psychiatric use is off-label. Some insurance plans cover SPRAVATO® for qualifying patients, subject to their clinical criteria, prior-authorization process, deductibles, and copayments.
Can I Continue My Current Antidepressant?
Many patients continue prescribed medication during treatment, but the plan depends on the individual medication, diagnosis, health history, and treatment selected. SPRAVATO® can currently be used as monotherapy or with an oral antidepressant for TRD. Patients should not stop or change any prescription without consulting the prescribing provider.
Do I Need a Psychiatrist’s Referral?
Three Rivers Wellness does not require a psychiatric referral to request an evaluation. Patients should bring or authorize access to relevant treatment records when possible. We encourage collaboration with existing providers so that care remains coordinated.
Key Takeaways
- Treatment-resistant depression is commonly identified after at least two adequate antidepressant trials have not provided enough improvement.
- TRD is a clinical description—not proof of one biological subtype or a prediction that recovery is impossible.
- Persistent symptoms should prompt a review of diagnosis, medication adequacy, adherence, side effects, and co-occurring conditions.
- IV ketamine has produced rapid antidepressant effects for some adults in clinical studies, but its psychiatric use is off-label.
- Improvement with IV ketamine may be partial or temporary, and an ideal long-term maintenance schedule has not been established.
- SPRAVATO® is FDA-approved for adult TRD as monotherapy or together with an oral antidepressant.
- SPRAVATO® and IV ketamine are distinct treatments with different protocols, risks, regulatory statuses, and insurance pathways.
- Three Rivers Wellness provides individualized evaluation and monitored outpatient treatment for qualifying Gallatin and Middle Tennessee patients.
Finding an Appropriate Next Step
Treatment-resistant depression has a name, but that name should not become a prediction about the future.
When several treatments have not provided enough relief, the safest next step is a thorough reassessment of the diagnosis, treatment history, current risks, and remaining options. For some patients, that discussion may include IV ketamine or SPRAVATO®. For others, a different change in care may be more appropriate.
At Three Rivers Wellness in Gallatin, we provide evaluations for adults who want a clear explanation of these treatments without guarantees or exaggerated claims. We discuss what the research supports, where uncertainty remains, and what the practical treatment process involves.
The next step begins with an informed conversation—not a commitment to treatment. Patients can review our services, learn more about the Three Rivers Wellness team, and schedule a consultation when they are ready to discuss their history.
About Darwin Sunday
Darwin Sunday, MSN, ACNP-BC, RN, is a co-founder of Three Rivers Wellness in Gallatin, Tennessee. Alongside co-founder David Baloun, he is a Vanderbilt University–trained Acute Care Nurse Practitioner with experience in emergency, urgent-care, and critical-care settings.
Their clinical backgrounds inform the practice’s emphasis on patient screening, preparation, monitoring, and individualized decision-making. Three Rivers Wellness recognizes that no treatment is appropriate for everyone and that depression outcomes vary substantially.
Medical Disclaimer
This article is for educational purposes only and does not constitute medical advice, diagnosis, or a recommendation for treatment. IV ketamine for depression is an off-label treatment. Treatment eligibility, risks, benefits, alternatives, and outcomes vary. Consult a qualified healthcare provider before starting, stopping, or changing medication or mental-health treatment.
If you are experiencing suicidal thoughts, a mental-health crisis, or immediate danger, call or text 988 to reach the 988 Suicide & Crisis Lifeline. Call 911 or go to the nearest emergency department when immediate assistance is needed.
Works Cited
Fava, M., Freeman, M. P., Flynn, M., et al. (2020). Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression. Molecular Psychiatry, 25(7), 1592–1603.
Gaynes, B. N., Lux, L., Gartlehner, G., et al. (2020). Defining treatment-resistant depression. Depression and Anxiety, 37(2), 134–145.
McIntyre, R. S., Alsuwaidan, M., Baune, B. T., et al. (2023). Treatment-resistant depression: Definition, prevalence, detection, management, and investigational interventions. World Psychiatry, 22(3), 394–412.
Murrough, J. W., Iosifescu, D. V., Chang, L. C., et al. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial. American Journal of Psychiatry, 170(10), 1134–1142.
National Institute of Mental Health. (n.d.). Questions and answers about the STAR*D study: All medication levels.
Sanacora, G., Frye, M. A., McDonald, W., et al. (2017). A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry, 74(4), 399–405.
U.S. Food and Drug Administration. (2025). SPRAVATO® prescribing information.