Approximately one in three people with major depressive disorder do not respond adequately to standard antidepressant medications — a clinical reality that SSRIs and SNRIs were not designed to solve, because they operate on the same neurological pathway regardless of how many times they are tried. At Minnesota Ketamine & Wellness Institute, we treat depression with ketamine infusion therapy and SPRAVATO® precisely because these treatments work through a fundamentally different mechanism than anything in the standard antidepressant toolkit, and that difference is what makes them relevant for patients who have not found adequate relief elsewhere.
Why Standard Antidepressants Work the Way They Do
SSRIs — selective serotonin reuptake inhibitors — are the most commonly prescribed class of antidepressants. They work by blocking the reabsorption of serotonin in the brain, increasing its availability in the gaps between neurons and allowing it to exert a longer-lasting effect on mood regulation. SNRIs — serotonin-norepinephrine reuptake inhibitors — work similarly but act on both serotonin and norepinephrine simultaneously. Research confirms the efficacy of both classes as first-line treatments for depression and anxiety disorders (National Institutes of Health).
The limitation of these medications is not that they are ineffective — it is that they operate on a specific set of pathways, and depression is not a single-pathway condition. For patients whose neurobiological depression involves systems that serotonin-targeted medications do not directly address, adding more medications of the same class is unlikely to produce a different result. This is the clinical reality that the concept of treatment-resistant depression — inadequate response to two or more antidepressant trials at adequate doses — was developed to describe.
How Ketamine Works Differently
Ketamine works by blocking NMDA receptors — N-methyl-D-aspartate receptors — in the glutamate system. Glutamate is the brain’s primary excitatory neurotransmitter, and the NMDA receptor is central to synaptic plasticity: the brain’s ability to strengthen, weaken, and reorganize connections between neurons. When NMDA receptors are modulated by ketamine, the result is a rapid increase in neuroplasticity — the formation of new neural connections and the restoration of communication pathways that depression, anxiety, and trauma have degraded over time (National Institutes of Health).
This mechanism is entirely distinct from how SSRIs and SNRIs work. Ketamine bypasses the serotonin route and acts directly on the glutamate system. The clinical consequence of that distinction is one of the most significant findings in psychiatric research in recent decades: ketamine can produce meaningful antidepressant effects within hours, not weeks. Research from the National Institute of Mental Health documents that ketamine restores pleasure-seeking behavior ahead of other antidepressant actions — meaning it reaches one of the core symptoms of depression, anhedonia (the inability to experience pleasure), faster than any serotonin-targeted medication currently available.
For patients who have spent months or years waiting for an antidepressant to work — or who have tried multiple medications without adequate response — this speed is not a minor detail. It is the point.
The Role of BDNF in Lasting Relief
One of the reasons ketamine’s effects may extend beyond the active infusion period is its impact on brain-derived neurotrophic factor, or BDNF — a protein essential for neuron growth and long-term mood regulation. Ketamine’s promotion of BDNF is thought to contribute to the structural changes in the brain that underlie sustained antidepressant effects.
Depression is associated with impaired memory and cognitive function, including deficits in areas of the brain that depend on BDNF for healthy neuron maintenance. By promoting neuroplasticity through NMDA receptor modulation, ketamine may address not just the chemical imbalance model of depression but the structural degradation that chronic depression produces over time. This does not mean ketamine reverses all effects of depression permanently or that results are identical across patients — individual results vary significantly — but it offers a biological explanation for why the treatment produces meaningful change in cases where serotonin-targeted medications have not.
What Ketamine Treatment for Depression Looks Like at Our Clinic
At Minnesota Ketamine & Wellness Institute, depression is treated with IV ketamine infusions — an initial series of six infusions administered over two to three weeks. Each infusion runs 40 minutes, with the first appointment requiring approximately one and a half to two hours for intake assessment and provider orientation. Subsequent sessions run approximately one hour each. After the initial series, most patients transition to maintenance infusions — typically scheduled once every two to eight weeks — at our maintenance rate of $400 per infusion.
Our clinical team, which includes our founder and CEO with 20 years of trauma center experience as a Certified Registered Nurse Anesthetist, a Medical Director with over 26 years of psychiatric practice, and licensed psychiatric nurse practitioners, conducts a thorough intake evaluation before any infusion begins. That evaluation includes a full medication review, assessment for contraindications, and an individualized treatment discussion. We do not use a one-size-fits-all protocol because depression does not present the same way in every patient.
SPRAVATO®: The FDA-Approved Option for Treatment-Resistant Depression
For patients whose depression meets the clinical threshold for treatment-resistant depression — defined as inadequate response to at least two antidepressant trials at appropriate doses — SPRAVATO® (esketamine nasal spray) is an FDA-approved treatment option available at our clinic. SPRAVATO® is the first medication of its kind approved specifically for treatment-resistant depression, and it is also approved for major depressive disorder with acute suicidal ideation or behavior.
SPRAVATO® works through the same glutamate/NMDA pathway as IV ketamine, and it is administered under the FDA’s Risk Evaluation and Mitigation Strategy (REMS) program, which requires in-clinic monitoring for approximately two hours after each session. Unlike IV ketamine, SPRAVATO® is covered by most major insurance plans for eligible patients, which makes it a meaningfully different financial proposition. Our team guides patients through the prior authorization process, and the Janssen CarePath Savings Card is available for eligible patients who need additional cost assistance.
Addressing the Stigma of Seeking Treatment Beyond Standard Antidepressants
One barrier we see consistently among patients considering ketamine therapy is the discomfort of moving beyond what their primary care physician or previous psychiatrist has offered. For many patients, seeking treatment at a specialized ketamine clinic carries an implicit concern that they are doing something unconventional or unproven — that pursuing ketamine means giving up on mainstream medicine.
That concern misreads both the evidence base and the clinical reality. Ketamine has been used safely in medical settings for decades, originally as a surgical anesthetic. Research from the National Institute of Mental Health documents that ketamine restores pleasure-seeking behavior ahead of other antidepressant actions — a finding that affirms its status as a clinically meaningful, peer-reviewed treatment. Pursuing ketamine therapy is not a departure from evidence-based care — it is evidence-based care through a different mechanism, for patients whose depression has not responded to the standard mechanism.
Addressing the Cost of Ketamine for Depression
IV ketamine infusions are an out-of-pocket expense for most patients. The initial series of six infusions is $500 per infusion; maintenance infusions are $400. Most HSA and FSA accounts can be used as a form of payment. A $250 service discount is available for military personnel, law enforcement officers, and front-line workers. Payment is per session — no prepayment of the full series is required.
SPRAVATO® follows a different coverage path: as an FDA-approved treatment for treatment-resistant depression, it is covered by most major insurance plans for eligible patients. For patients who qualify for SPRAVATO®, the insurance picture is meaningfully better than for IV ketamine. We help patients determine which treatment pathway makes clinical and financial sense for their individual situation — discuss your options with your provider at consultation.
Frequently Asked Questions
How is ketamine different from regular antidepressants? Standard antidepressants work on the serotonin or norepinephrine systems and typically require four to eight weeks to produce noticeable effects. Ketamine acts on the glutamate system through NMDA receptor modulation and can produce antidepressant effects within hours. The mechanism is entirely distinct, which is why ketamine may help patients who have not responded to multiple antidepressant trials.
Does ketamine work for all types of depression? Ketamine and SPRAVATO® are used at our clinic for major depressive disorder, treatment-resistant depression, and related conditions confirmed in our intake assessment. Results vary by individual, and not every patient who undergoes ketamine therapy will experience significant symptom relief. A thorough clinical evaluation at intake helps determine whether ketamine is an appropriate fit for your specific presentation.
Is SPRAVATO® the same as ketamine infusion therapy? SPRAVATO® (esketamine) is derived from ketamine and works through the same glutamate/NMDA pathway, but it is a nasal spray rather than an IV infusion, and it has received FDA approval for specific indications — treatment-resistant depression and MDD with acute suicidal ideation — that IV ketamine has not. The two treatments have different administration protocols, monitoring requirements, insurance coverage situations, and clinical profiles. Your provider will discuss which option is more appropriate given your history.
Can I try ketamine while still taking my current antidepressant? Possibly, depending on what you are taking. Some medications interact with ketamine in ways that affect efficacy or safety, and others are compatible with concurrent use. This is evaluated during the intake medication review. We do not make blanket recommendations — medication decisions are individualized and made collaboratively with your provider.
How long do the effects of ketamine last for depression? The effects of ketamine can last from a few weeks to a few months, with considerable individual variation. The initial six-infusion series is designed to build a cumulative neurological foundation, and maintenance infusions — typically scheduled every two to eight weeks — help sustain those effects over time. Results vary by individual, and the maintenance schedule is adjusted based on your ongoing response.
Key Takeaways
- Ketamine works on the glutamate system through NMDA receptor modulation — a fundamentally different mechanism than SSRIs and SNRIs, which target serotonin and norepinephrine pathways.
- Ketamine can produce antidepressant effects within hours, compared to the four-to-eight-week timeline of standard antidepressants; results vary by individual.
- SPRAVATO® (esketamine nasal spray) is FDA-approved for treatment-resistant depression and MDD with acute suicidal ideation, and is covered by most major insurance plans for eligible patients.
- IV ketamine infusions are an out-of-pocket expense for most patients; SPRAVATO® follows a different insurance coverage path as an FDA-approved treatment.
- Pursuing ketamine therapy is evidence-based care through a different neurological mechanism — not a departure from mainstream medicine.
Depression that has not responded to multiple antidepressants is not a personal failing — it is a clinical signal that the mechanism driving it may require a different approach. At Minnesota Ketamine & Wellness Institute, we offer that different approach through IV ketamine infusions and SPRAVATO®, guided by a team with deep clinical experience in both. Call us at 612-502-2800 or complete the consultation form on our website to find out whether ketamine therapy or SPRAVATO® may be right for your situation.
References
- National Institutes of Health. NMDA receptor / glutamate system and ketamine’s mechanism of action. https://pmc.ncbi.nlm.nih.gov/articles/PMC5148235/
- National Institutes of Health. SSRIs — efficacy and limitations. https://pmc.ncbi.nlm.nih.gov/articles/PMC8395812/
- National Institute of Mental Health. Rapid agent restores pleasure-seeking ahead of other antidepressant action. https://www.nimh.nih.gov/news/science-updates/2014/rapid-agent-restores-pleasure-seeking-ahead-of-other-antidepressant-action
Medical Disclaimer: The information in this blog is provided for educational purposes only and does not constitute medical advice. Ketamine infusion therapy and SPRAVATO® treatment at Minnesota Ketamine & Wellness Institute are medical procedures that should only be pursued under the supervision of a licensed provider familiar with your complete medical and psychiatric history. Individual results vary. Neither ketamine nor SPRAVATO® is appropriate for every patient — a thorough clinical evaluation is required before any treatment begins. 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.