When depression persists despite well-conducted treatment, the next step should be careful reassessment rather than a rush toward a new intervention. Treatment history, current symptoms, physical health, goals, and available support all help determine whether another approach deserves consideration.
Find a Journey Clinical therapist who specializes in ketamine-assisted psychotherapy and can help you explore whether this approach fits your clinical picture.
Treatment-resistant depression ketamine care may combine medically supervised ketamine treatment with structured psychotherapy for adults whose depression has not responded adequately to prior treatments. Research suggests ketamine can produce more rapid antidepressant effects than many traditional medications, but response varies and the treatment requires informed consent, clinical monitoring, and ongoing psychiatric care.
Ketamine-Assisted Psychotherapy adds a therapeutic framework around the medical intervention, giving patients and clinicians space to consider symptoms, functioning, and meaningful goals together. Understanding how treatment resistance is defined provides the foundation for evaluating evidence, potential eligibility, and how this option compares with standard depression treatments.
What Is Treatment-Resistant Depression?
Journey Clinical defines treatment-resistant depression (TRD) as major depressive disorder that has not reached remission after at least two adequate trials of different antidepressants at appropriate dose and duration. This clinical distinction guides the next step in care, whether that involves reassessment, augmentation, or a referral for advanced treatment options such as ketamine-assisted psychotherapy.
Treatment-resistant depression (TRD) generally refers to major depressive disorder that has not reached remission after at least two adequate trials of different antidepressants. An adequate trial considers whether the medication was taken at an appropriate therapeutic dose for a sufficient duration, while also accounting for tolerability and adherence. The definition is clinical rather than a judgment about a person's effort or the value of prior care. Clinical references commonly describe TRD as two prior treatment failures at an adequate dose and duration.
How common is treatment resistance?
Estimates vary depending on the population studied and how treatment response is defined. Research commonly places the proportion of depressed patients who meet criteria for TRD at roughly 10% to 20%. Other analyses suggest that about 30% of people with major depressive disorder do not respond adequately to two or more antidepressants. These figures describe patterns across groups, not a prediction of what will happen for any individual patient.
Why the distinction matters
When symptoms continue despite multiple well-delivered treatment attempts, the effects can extend beyond mood. TRD is associated with meaningful functional impairment, which may affect work, relationships, sleep, self-care, and the ability to participate in treatment. It is also associated with greater healthcare utilization, including the need for additional appointments, medication changes, monitoring, and coordinated support. The clinical goal is therefore broader than reducing a score on a symptom measure. It includes restoring daily functioning and identifying a plan that reflects the patient's history, needs, preferences, and safety considerations.
A TRD designation does not mean that improvement is impossible, and it does not automatically determine which treatment should come next. Clinicians typically review prior medication trials, diagnoses, co-occurring conditions, current symptoms, treatment goals, and practical support before considering another intervention. For readers exploring ketamine-assisted psychotherapy, a careful review of eligibility criteria is an important next step.
Because treatment response is individual and the evidence base continues to develop. Decisions about treatment-resistant depression ketamine care should be made with qualified medical and mental health professionals rather than from a diagnosis label alone.
How Ketamine Works for Treatment-Resistant Depression
Journey Clinical approaches ketamine as a treatment that works differently from traditional antidepressants: it influences glutamate signaling and NMDA receptor activity rather than serotonin or norepinephrine pathways. This distinct mechanism may produce symptom changes within hours to days, unlike the weeks typically required for SSRIs to reach full effect.
Ketamine differs from traditional antidepressants because its primary action is not on the monoamine systems targeted by many selective serotonin reuptake inhibitors (SSRIs). Instead, it influences glutamate signaling, an excitatory neurotransmitter involved in communication between brain cells. This distinction helps explain why ketamine is studied as a rapid-acting option for some people with treatment-resistant depression. While SSRIs commonly require several weeks before their full effects can be evaluated.
NMDA receptor antagonism and glutamate signaling
Ketamine temporarily blocks the N-methyl-D-aspartate (NMDA) receptor, a receptor involved in glutamate transmission. This action can produce downstream changes in signaling that affect how neurons communicate. Research from the National Institute of Mental Health describes ketamine's interaction with a brain receptor as part of a process that can reset neural pathways associated with depression. The same research identifies NMDA receptor antagonism and synaptic plasticity as important parts of ketamine's mechanism.
In practical terms, NMDA antagonism may trigger a short-term increase in glutamate activity in specific neural circuits. That surge can activate pathways associated with the production of proteins that support synaptic function. The result is not simply more neurotransmitter in the brain. It is a change in the connections and signaling patterns that influence mood, learning, and adaptation. Researchers describe this process as promoting synaptic plasticity, which can support the formation or strengthening of neural connections.
Why the timing can differ from SSRIs
SSRIs primarily adjust serotonin availability and generally build their therapeutic effect gradually. Clinicians often assess response over weeks, while ketamine has demonstrated antidepressant effects within hours to days in clinical research. This faster time course is one reason ketamine has been investigated for depression that has not responded adequately to conventional treatments.
Rapid onset does not mean a universal or permanent response. The duration of benefit varies among patients, and individual response can be heterogeneous. Ketamine treatment therefore belongs within a broader clinical plan that includes appropriate assessment, monitoring, informed consent, and follow-up. When psychotherapy is part of care, the biological effects of ketamine can be paired with structured support to help patients reflect on symptoms, behavior patterns, and treatment goals.
Read the National Institute of Mental Health's explanation of ketamine's mechanism, along with the research review describing ketamine as a rapid-acting antidepressant distinct from monoamine-based therapies.
Clinical Evidence: What the Research Shows
Journey Clinical reviews the evidence base for treatment-resistant depression ketamine as promising but measured: multiple studies and meta-analyses report rapid antidepressant effects, yet response varies and long-term outcomes require further study. The strongest data come from controlled trials and systematic reviews that include hundreds of patients with TRD.
Research on treatment-resistant depression ketamine has moved from small early trials toward broader clinical studies and evidence reviews. The findings are encouraging, particularly around speed of symptom change, but they do not mean ketamine works for everyone or replaces careful psychiatric assessment. Outcomes vary, and clinical decisions should account for a person's history, current symptoms, medical needs, and treatment goals.
Findings from the Bio-K study
The Bio-K study, conducted across four clinics in Michigan, Maryland, and Minnesota, included 74 people with severe depression. After three ketamine infusions delivered over 11 days, 52% of participants reached remission, while another 15% experienced a partial response. The population was clinically complex: more than 80% reported suicidality, a feature that would have excluded many of them from conventional depression treatment studies. Among participants who frequently experienced suicidal thoughts before treatment, half reported a dramatic reduction in those impulses.
These results are clinically important, while still requiring context. The study was not a guarantee of remission, and its findings do not establish that the same response will occur for every patient. They do show why researchers continue to study ketamine as a rapid-acting option for people whose depression has not improved with other approaches. Michigan Medicine's report on the Bio-K study also emphasizes that major questions about response and longer-term outcomes remain.
What larger evidence reviews suggest
A systematic review examined 24 manuscripts involving 416 patients with treatment-resistant depression. Most of the included studies reported rapid antidepressant effects, supporting further investigation of ketamine's role in depression care. A review of this kind is useful because it brings multiple studies together, but it also inherits their limitations. The studies may differ in design, patient characteristics, outcome measures, and follow-up periods, which makes it difficult to treat one summary number as a universal expectation. Researchers commonly track outcomes with standardized measures such as the Montgomery-Asberg Depression Rating Scale, alongside changes in daily functioning and quality of life.
For a clinician or patient, the practical meaning is more measured than a headline statistic. Ketamine may produce improvement more quickly than many conventional antidepressants, yet the duration and degree of benefit differ from person to person. Ongoing evaluation is needed to determine whether symptom changes are sustained and how they fit within a broader care plan. For a deeper review of the literature, see KAP research and outcomes.
Comparing IV ketamine and intranasal esketamine
A retrospective Mass General Brigham comparison study analyzed 153 adults treated at McLean Hospital: 111 received IV ketamine and 42 received intranasal esketamine. Both approaches reduced depression severity, while the IV ketamine group showed a 49.22% reduction in depression scores and relatively faster, greater improvement in the study's analysis. The treatments were administered twice weekly during a four- to five-week induction period.
Because this was a retrospective cohort study rather than a randomized trial, the results should not be read as a direct ranking of one treatment for every patient. Esketamine is an FDA-approved nasal spray for treatment-resistant depression. IV ketamine is used off-label under clinical judgment and professional oversight. The appropriate option depends on the full clinical picture, informed consent, monitoring, and the treatment plan surrounding the intervention.
Ketamine vs Esketamine: Key Differences for TRD
Journey Clinical distinguishes IV ketamine from esketamine (Spravato) based on FDA approval status, route of administration, and evidence profile. While both are derived from the same compound, their clinical applications differ in ways that matter for treatment decisions, insurance coverage, and treatment setting.
IV ketamine and esketamine nasal spray are related treatments, but they are not interchangeable in how they are approved, delivered, monitored, or covered. Both may be considered within a broader plan for treatment-resistant depression, with the choice guided by clinical history, access, treatment goals, and the prescribing clinician's judgment. A retrospective study of 153 adults treated at McLean Hospital found that both approaches reduced depression severity. While IV ketamine produced relatively faster and greater improvement in that cohort. The findings support a balanced discussion rather than a single preferred option.
| Factor | IV ketamine | Esketamine nasal spray |
|---|---|---|
| Route of administration | Administered by intravenous infusion in a clinical setting. | Administered as a prescription nasal spray under an approved monitoring program. |
| FDA approval status | Used off-label for depression, based on clinical evidence and professional judgment. | FDA-approved for adults with treatment-resistant depression. Johns Hopkins Medicine describes esketamine treatment and its clinical use. |
| Typical setting | A clinic or medical office with supervision during the infusion and recovery period. | A certified healthcare setting where the patient remains under observation after use. |
| Induction frequency | In the Mass General Brigham comparison, infusions were given twice weekly during a four- to five-week induction period. | The same comparison evaluated esketamine twice weekly during a four- to five-week induction period. |
| Onset and response | May produce improvement within hours to days. In the Mass General Brigham cohort, depression scores fell 49.22% with IV ketamine, and improvement was relatively faster. | Can also reduce symptom severity, although improvement was slower on average in the Mass General Brigham comparison. |
| Insurance coverage | Coverage varies because IV use for depression is off-label. Patients may need to review self-pay terms and benefits directly with the practice and insurer. | Coverage depends on the plan, authorization requirements, and the patient's benefits. FDA approval does not guarantee coverage. |
These differences matter when evaluating treatment-resistant depression ketamine options. The McLean analysis was retrospective, so its results do not establish that one treatment will work better for every person. A qualified medical team can explain the evidence, monitoring requirements, alternatives, and expected financial responsibilities before treatment begins.
The Role of Psychotherapy in Ketamine Treatment for TRD
Journey Clinical integrates ketamine treatment within a structured psychotherapy framework called ketamine-assisted psychotherapy (KAP), where medical and therapeutic care work together rather than as separate services. This model includes preparation, medication sessions with therapist support, and integration sessions to translate insights into lasting change.
Ketamine-assisted psychotherapy (KAP) pairs a medically supervised ketamine treatment with structured psychotherapy before, during, and after sessions. This framework gives patients more than a temporary change in symptoms. It creates a supported setting for understanding difficult experiences, identifying patterns, and translating new perspectives into daily life. Research describes KAP as an integrated model in which medical treatment and psychotherapeutic support work together, rather than as separate services (research on ketamine-assisted psychotherapy).
Preparation builds a clear therapeutic foundation
Preparation generally includes one or two sessions with the therapist. These meetings establish the therapeutic relationship, review what to expect, and support informed consent and realistic treatment goals. Patients may also identify an intention for the work, such as becoming more aware of a recurring pattern or exploring how depression affects relationships and daily functioning. An intention is not a promise of a particular outcome. It is a point of focus that can help the patient and therapist notice meaningful material as treatment progresses.
Dosing sessions provide support while treatment is underway
In Journey Clinical's KAP framework, patients commonly complete six to eight dosing sessions using prescribed sublingual lozenges. Sessions typically last two to three hours, with the therapist present to provide a calm, structured, and clinically attentive setting. The medical team remains responsible for medical evaluation, prescribing, and monitoring, while the therapist supports the psychotherapeutic process. This collaborative model reflects the importance of professional supervision and coordinated care when ketamine is used for treatment-resistant depression.
The therapist does not need to direct every moment of a session. Instead, the work may involve maintaining a steady presence. Helping the patient stay oriented to the agreed therapeutic frame, and observing themes that can be explored more fully afterward. The approach should remain patient-centered and responsive to the individual's clinical needs.
Integration helps insights become practical change
Integration sessions give patients time to process what arose during treatment and connect those observations to their everyday lives. The therapist can help distinguish a useful insight from a conclusion that needs more reflection. Then identify manageable steps for applying the learning to behavior, relationships, or coping patterns. This process may also reinforce healthier neural pathways as new responses are practiced over time. A review of KAP literature describes integration as a way to anchor insights from treatment in daily life and consolidate therapeutic gains (source on KAP integration).
Ketamine alone may produce rapid biological effects, but those effects do not automatically supply context, skills, or ongoing support. Psychotherapy helps patients examine what changes, build meaning around the experience, and continue working after the acute effects have passed. The evidence does not mean every patient will respond in the same way, or that psychotherapy guarantees a particular result. It does support placing ketamine within a broader, structured psychiatric and psychotherapeutic care plan. For clinicians interested in this collaborative model, learn more about how therapists can add KAP to their practice.
Who May Benefit From Ketamine for Treatment-Resistant Depression?
Journey Clinical considers adult patients with confirmed TRD who have not responded to at least two adequate antidepressant trials as potential candidates for ketamine-assisted psychotherapy, following a thorough medical and psychiatric screening. Eligibility is determined individually based on clinical history, safety factors, and ability to participate in ongoing monitoring.
Ketamine treatment may be considered for adults whose depression has not improved enough after at least two adequate trials of different antidepressants. This history is central to how clinicians define treatment-resistant depression, but it does not make someone automatically eligible. The decision depends on the person's symptoms, medical history, current medications, treatment goals, and ability to participate in ongoing monitoring and psychotherapy.
Because ketamine is a controlled substance and can affect blood pressure, perception, and alertness, careful assessment is essential. A clinician may recommend against treatment for someone with a history of psychosis or schizophrenia, active substance abuse, or uncontrolled hypertension. These factors require particular caution and may make ketamine treatment inappropriate. Other medical or psychiatric considerations can also affect the recommendation. The Cleveland Clinic's overview of ketamine therapy describes its clinical uses, controlled-substance status, and potential side effects.
What the screening process includes
Screening typically begins with a detailed review of prior depression treatments. The medical team may ask which antidepressants were tried, how long each was taken, how consistently it was used, and what benefits or adverse effects occurred. The review should also cover psychiatric history, physical health conditions, blood pressure, current medications, substance use, and any history that could increase risk.
Informed consent is another important part of the process. Before treatment begins, the patient should receive a clear explanation of the expected goals, possible benefits, known risks, alternatives, and monitoring requirements. This conversation gives the patient an opportunity to ask questions and decide whether the treatment fits their circumstances. It also helps establish realistic expectations: ketamine is not appropriate for everyone, and a clinical response cannot be guaranteed.
A collaborative eligibility decision
When treatment is considered appropriate, medical oversight and psychotherapy should work together. The medical team evaluates safety and monitors the treatment, while a licensed therapist can support preparation, the treatment session, and integration. Patients who want additional context can learn more about patient eligibility and the care process before deciding whether to request an evaluation.
Safety Profile and Side Effects of Ketamine for TRD
Journey Clinical prioritizes patient safety through comprehensive screening, informed consent, medical supervision during administration, and ongoing follow-up. Ketamine is a Schedule III controlled substance, and its use for depression requires clinical oversight rather than unsupervised self-administration.
When ketamine is considered for treatment-resistant depression, safety depends on careful screening, informed consent, clinical oversight, and follow-up. The medication is a Schedule III controlled substance, so its use requires appropriate medical judgment and monitoring rather than unsupervised self-administration. Professional supervision is recommended because its effects can change perception and coordination for a limited period. Clinical reference materials describe supervised administration as a core part of responsible care.
What side effects may occur?
Some people experience dissociation during or shortly after administration. This can feel like a temporary sense of detachment or altered perception. Dizziness and blurred vision may also occur. Changes in blood pressure, nausea, and other short-term physical effects are possible. These effects are generally transient and manageable in a clinical setting, where a trained team can observe the patient and respond if concerns arise.
Monitoring is not an optional add-on. Blood pressure checks and other cardiovascular observations are standard safety measures during administration. The care team also assesses how the patient is responding before determining whether it is appropriate to continue or conclude a session. Ongoing follow-up helps clinicians evaluate both benefit and tolerability over time.
Screening and contraindications
Ketamine may not be appropriate for everyone. Relevant concerns can include uncontrolled hypertension, a history of psychosis or schizophrenia, and active substance use problems. A clinician should review medical history, current medications, psychiatric symptoms, and treatment goals before making an individualized recommendation. Informed consent should address potential benefits, risks, and alternatives, not present ketamine as a guaranteed outcome.
These safeguards are familiar elements of clinical practice, not signs that treatment is inherently unsafe. For clinicians comparing care models, our guide to Spravato for treatment-resistant depression provides additional context on supervised treatment and the role of coordinated care. A structured medical and psychotherapy framework gives patients space to ask questions, report side effects, and make decisions with appropriate support.
If you or a patient is living with treatment-resistant depression, learn more about the Journey Clinical approach to KAP and how to begin the evaluation process.
Frequently Asked Questions
What is treatment-resistant depression?
Treatment-resistant depression generally refers to major depressive disorder that has not reached remission after at least two adequate trials of different antidepressants, with appropriate dose and duration. A clinician should confirm the diagnosis, review prior treatments, and consider other factors before discussing next-step care. The National Center for Biotechnology Information summarizes this commonly used definition.
How does ketamine work for treatment-resistant depression?
Ketamine temporarily blocks NMDA receptors and influences glutamate signaling, which may support changes in neural pathways associated with mood. Its antidepressant effects can appear more quickly than those of many traditional antidepressants, although response varies by patient. Research continues to clarify how these effects develop and how long they last. The National Institute of Mental Health describes current findings on ketamine's mechanism.
Is ketamine FDA-approved for depression?
Esketamine, a specific form of ketamine delivered as a nasal spray, is FDA-approved for treatment-resistant depression under appropriate clinical oversight. Intravenous ketamine is used off-label for depression, based on a clinician's judgment and the patient's circumstances. Ketamine-assisted psychotherapy may combine medical care with structured preparation and therapeutic support, but it does not replace individualized evaluation.
Who may be considered for ketamine-assisted psychotherapy?
Potential candidates are evaluated individually after a clinical history, medication review, safety screening, and informed-consent process. A history of psychosis, active substance misuse, or uncontrolled high blood pressure may affect whether ketamine is appropriate. Because dissociation, dizziness, nausea, and temporary blood-pressure changes can occur, administration requires professional supervision. NCBI outlines clinical supervision and safety considerations.
Ready to take the next step?
Ready to explore whether ketamine-assisted psychotherapy is right for you or your patient? Contact Journey Clinical to begin the evaluation process. Thoughtful collaboration can help clinicians support patients considering ketamine-assisted psychotherapy while keeping medical and therapeutic care connected. If you are a licensed therapist interested in joining Journey Clinical, or a provider looking to refer a patient, get started with Journey Clinical.