Ketamine and Esketamine (Spravato) for Depression: How They Work, What to Expect, and What the Evidence Shows

Ketamine is an anesthetic medication that has been used in surgical and emergency medicine since the 1970s. Over the past two decades, researchers discovered that ketamine — administered at doses far lower than those used for anesthesia — produces rapid antidepressant effects, often within hours rather than the weeks required by traditional antidepressants. This discovery has been described as one of the most significant advances in the treatment of depression in decades.

There are two forms of ketamine relevant to mental health treatment:

• Racemic ketamine (IV ketamine): This is the original formulation, containing equal parts of two mirror-image molecules — "R-ketamine" and "S-ketamine." When used for depression, it is most commonly administered as a slow intravenous (IV) infusion in specialized clinics. This use is considered off-label, meaning the FDA has approved ketamine as an anesthetic, but not specifically for depression. Off-label prescribing is a legal and common medical practice.
• Esketamine (brand name Spravato): This is a nasal spray containing only the S-ketamine molecule. In 2019, the FDA approved Spravato specifically for treatment-resistant depression (TRD) in adults, and in 2020 it received an additional indication for major depressive disorder with acute suicidal ideation or behavior. Spravato is the only ketamine-based product with formal FDA approval for a psychiatric indication.

Both forms target similar brain mechanisms, but they differ in how they are administered, regulated, and covered by insurance — distinctions that carry significant practical implications for patients.

Traditional antidepressants — such as SSRIs like fluoxetine (Prozac) or sertraline (Zoloft) — work primarily by modulating serotonin, norepinephrine, or dopamine signaling. Ketamine operates through a fundamentally different mechanism, which is a major reason it has generated so much scientific interest.

Glutamate and NMDA receptor antagonism: Ketamine's primary action is blocking N-methyl-D-aspartate (NMDA) receptors, which are receptors for glutamate — the brain's most abundant excitatory neurotransmitter. By temporarily blocking these receptors, ketamine triggers a cascade of downstream effects that are believed to underlie its rapid antidepressant properties.

Synaptic plasticity and BDNF: One of the most important downstream effects is a surge in brain-derived neurotrophic factor (BDNF), a protein that promotes the growth and strengthening of synaptic connections between neurons. Research in both animal models and humans suggests that depression is associated with synaptic atrophy — a loss of connections — particularly in the prefrontal cortex and hippocampus. Ketamine appears to rapidly restore these connections, a process called synaptogenesis.

The mTOR signaling pathway: Ketamine activates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in protein synthesis needed for the formation of new synaptic connections. This mechanism is distinct from anything seen with conventional antidepressants and helps explain why ketamine's effects can be felt within hours.

Other mechanisms under investigation: Researchers are also studying ketamine's effects on the opioid system, anti-inflammatory pathways, and the default mode network — a brain network associated with rumination and self-referential thinking. These lines of research are still emerging, and no single mechanism fully accounts for ketamine's complex effects.

Notably, while these mechanisms are well-supported by preclinical and clinical research, our understanding of exactly how ketamine relieves depression continues to evolve.

FDA-approved indication (Spravato/esketamine):

• Treatment-resistant depression (TRD): Defined as major depressive disorder (MDD) that has not responded adequately to at least two different antidepressant medications taken at adequate doses for adequate durations during the current episode.
• Major depressive disorder with acute suicidal ideation or behavior: For adults who require rapid reduction of depressive symptoms, particularly when suicidal thinking is present.

Off-label uses of IV ketamine (supported by varying levels of evidence):

• Treatment-resistant depression: IV ketamine is widely used off-label for TRD, and its evidence base for this indication is substantial, though it lacks a formal FDA approval for this purpose.
• Acute suicidality: Research suggests IV ketamine can rapidly reduce suicidal ideation, sometimes within hours — a potentially life-saving property given that most antidepressants take weeks to work.
• Bipolar depression: Some clinical studies have demonstrated benefits for the depressive phase of bipolar disorder, though this use requires careful psychiatric supervision due to theoretical concerns about triggering mania.
• Post-traumatic stress disorder (PTSD): Emerging research suggests potential benefits, but the evidence is less robust than for depression, and clinical trials are ongoing.
• Obsessive-compulsive disorder (OCD): Preliminary studies have shown short-term benefit, but evidence remains limited.
• Chronic pain syndromes: Ketamine has a well-established role in pain management, and some patients with comorbid depression and chronic pain may benefit from treatment that addresses both conditions.

The strength of evidence varies considerably across these conditions. The most robust data support ketamine's use for treatment-resistant depression and acute suicidal ideation. Individuals considering ketamine for other conditions should discuss the available evidence with a qualified mental health provider.

The treatment experience differs depending on whether you are receiving IV ketamine or Spravato (esketamine nasal spray), but both share important commonalities.

IV Ketamine Infusions:

• Setting: Administered in specialized ketamine clinics or, less commonly, in hospital settings. You will typically recline in a comfortable chair in a calm, dimly lit room.
• Dosing: The standard antidepressant dose is approximately 0.5 mg/kg infused over 40 minutes, though some providers adjust this based on response and tolerability.
• Typical protocol: An initial series of six infusions over two to three weeks is common. Maintenance infusions — ranging from every few weeks to every few months — are often recommended based on individual response.
• Monitoring: Vital signs (blood pressure, heart rate, oxygen saturation) are monitored throughout. A medical professional is present for the duration.
• Duration: Including preparation and post-infusion observation, expect each visit to last approximately 90 minutes to two hours.

Spravato (Esketamine Nasal Spray):

• Setting: Administered exclusively in REMS-certified healthcare settings (REMS stands for Risk Evaluation and Mitigation Strategy). You cannot take Spravato home — each dose must be self-administered under direct medical supervision.
• Dosing: Available in 56 mg and 84 mg doses. Treatment begins with twice-weekly sessions for four weeks, then transitions to weekly sessions for four weeks, and eventually moves to once weekly or once every two weeks.
• Monitoring: Patients must remain in the healthcare setting for at least two hours after each dose for observation of blood pressure changes and dissociative effects.
• Driving restriction: Patients must not drive or operate heavy machinery until the day after each treatment session.

The subjective experience:

During a ketamine or esketamine session, most people experience some degree of dissociation — a feeling of detachment from one's body or surroundings. This can range from mild (feeling "floaty" or dreamlike) to more intense (distorted perceptions of time, space, or self). Other common experiences include dizziness, nausea, blurred vision, and a temporary increase in blood pressure. Some patients find the dissociative experience uncomfortable, while others describe it as neutral or even insightful. These effects are transient and typically resolve within one to two hours.

It is strongly recommended — and required for Spravato — that patients arrange transportation home after each session.

The evidence supporting ketamine and esketamine for depression is among the strongest for any psychiatric treatment introduced in recent decades, though important nuances exist.

Esketamine (Spravato) — Phase III clinical trials:

The FDA's approval of Spravato was based on multiple large randomized controlled trials. In the pivotal trials for treatment-resistant depression, Spravato combined with a newly initiated oral antidepressant was significantly more effective than a newly initiated oral antidepressant plus placebo nasal spray. A long-term maintenance study (the SUSTAIN-1 trial) demonstrated that patients who continued Spravato had significantly lower relapse rates compared to those switched to placebo — approximately 27% relapse versus 45% over a 16-week period.

For the acute suicidality indication, the ASPIRE I and ASPIRE II trials showed that Spravato combined with standard of care produced rapid reductions in depressive symptoms within 24 hours, though the difference on suicidal ideation-specific measures was less consistent across studies.

IV Ketamine — Meta-analyses and systematic reviews:

Multiple meta-analyses have found that a single IV ketamine infusion produces rapid antidepressant effects, with response rates (typically defined as a 50% or greater reduction in depression severity scores) ranging from approximately 50% to 70% within the first 24 hours. However, the effects of a single infusion are transient, with most patients experiencing a return of symptoms within one to two weeks without additional treatment. Serial infusions and maintenance protocols extend the duration of benefit, though the optimal long-term dosing strategy remains an active area of research.

Speed of onset: Perhaps ketamine's most remarkable property is its speed. Research consistently shows measurable improvement within hours to a single day — a stark contrast to the four to eight weeks typically required for conventional antidepressants. This rapid onset is particularly valuable for patients in acute crisis.

Limitations of the evidence:

• Long-term data are limited. Most controlled studies have followed patients for weeks to months, not years. The long-term safety and efficacy of repeated ketamine treatments are not fully established.
• Blinding challenges: Because ketamine produces noticeable dissociative effects, it is difficult to create a truly "blinded" placebo condition in clinical trials. Some researchers argue this could inflate apparent efficacy due to expectancy effects.
• Durability: Without ongoing maintenance treatment, relapse is common. This raises questions about dependency on repeated treatments and the associated long-term costs.
• Head-to-head comparisons: There is limited data directly comparing IV ketamine to esketamine, or comparing either to other treatment strategies like electroconvulsive therapy (ECT).

Common short-term side effects:

• Dissociation: Experienced by a majority of patients; typically resolves within two hours.
• Elevated blood pressure: Transient increases are common and are the primary reason for post-dose monitoring. Patients with uncontrolled hypertension or a history of aneurysmal vascular disease are generally excluded from treatment.
• Nausea and vomiting: Reported in roughly 25–30% of patients; often manageable with anti-nausea medication.
• Dizziness, sedation, and headache: Common but generally mild and short-lived.
• Anxiety during the session: Some patients experience transient anxiety or agitation, particularly during the dissociative phase.

Serious concerns and contraindications:

• Abuse potential: Ketamine is a Schedule III controlled substance. It has known abuse liability, and chronic recreational use is associated with bladder damage (interstitial cystitis), cognitive impairment, and psychological dependence. The clinical doses used for depression are substantially lower than recreational doses, and the supervised treatment setting is designed to mitigate misuse risk. However, this is a legitimate concern that requires ongoing monitoring.
• Psychotic disorders: Ketamine is generally contraindicated in individuals with active psychosis or a history of psychotic disorders (such as schizophrenia), as it can exacerbate psychotic symptoms.
• Substance use disorders: A history of ketamine or other substance misuse requires careful risk-benefit analysis. Some providers will treat patients with substance use histories under close supervision, while others consider it a relative contraindication.
• Pregnancy: Ketamine and esketamine are not recommended during pregnancy due to potential risks to fetal development.
• Cognitive effects: Research on long-term cognitive effects of repeated sub-anesthetic ketamine use is limited. Some studies suggest no significant cognitive impairment at clinical doses, but this remains an area of active investigation.

The unregulated clinic landscape:

Because IV ketamine is used off-label, the quality and safety standards of ketamine clinics vary considerably. Some clinics are operated by board-certified psychiatrists with robust safety protocols, while others have minimal psychiatric oversight. Patients should scrutinize the qualifications of providers, the presence of emergency preparedness procedures, and whether psychiatric follow-up is integrated into the treatment plan.

Finding a reputable provider is one of the most important steps in pursuing ketamine treatment. Here is what to look for:

For Spravato (esketamine):

• Use the official Spravato REMS program website to locate certified treatment centers. Only healthcare settings enrolled in the REMS program are authorized to administer Spravato.
• Treatment is typically provided within psychiatric practices, community mental health clinics, or hospital-affiliated outpatient programs.
• Ensure that a psychiatrist or psychiatric nurse practitioner is involved in your care — not just during the nasal spray administration, but for overall treatment planning.

For IV ketamine:

• Look for clinics staffed by board-certified psychiatrists, anesthesiologists, or emergency medicine physicians with specific training in ketamine for mental health.
• Ask whether the clinic conducts a thorough psychiatric evaluation before initiating treatment, including screening for psychotic disorders, substance use disorders, and cardiovascular risk factors.
• Inquire about the clinic's emergency protocols — is resuscitation equipment available? Is staff trained in advanced cardiac life support (ACLS)?
• Ask whether the clinic coordinates with your existing mental health providers and whether psychotherapy is offered as a complement to ketamine treatment.
• Be cautious of clinics that aggressively market ketamine as a "cure" or that downplay risks. Evidence-based providers will present a balanced picture.

Professional organizations and directories:

• The American Society of Ketamine Physicians, Psychotherapists and Practitioners (ASKP3) maintains a provider directory.
• The American Psychiatric Association (APA) has published consensus statements on ketamine use that can help patients understand best practices.

It is reasonable to consult with more than one provider before committing to a treatment plan. A qualified provider will welcome questions about their training, protocols, and outcome tracking.

Cost remains one of the most significant barriers to ketamine-based treatment, and the financial landscape differs substantially between the two formulations.

Spravato (esketamine):

• Because Spravato is FDA-approved, it is more likely to be covered by insurance, including Medicare and many commercial plans — but coverage is not universal, and prior authorization requirements are common.
• Even with insurance, copays and the requirement for in-office administration (including the two-hour monitoring period) create substantial costs and time demands.
• Without insurance, the medication cost alone can range from approximately $600 to $900 per session, not including facility fees.
• Janssen (the manufacturer) offers a patient savings program for eligible commercially insured patients and a separate program for uninsured patients, which may reduce out-of-pocket costs.

IV ketamine:

• Because this use is off-label, most insurance plans do not cover IV ketamine infusions for depression. Patients typically pay entirely out of pocket.
• Costs range from approximately $400 to $800 per infusion, depending on geographic location and clinic pricing. An initial six-infusion series can therefore cost $2,400 to $4,800 or more, with additional costs for maintenance infusions.
• Some clinics offer payment plans or package pricing for the initial infusion series.

Other formulations:

• Some providers prescribe oral, sublingual, or intranasal racemic ketamine compounded by specialty pharmacies for at-home use. These tend to be less expensive (sometimes $50–$150 per month) but involve different risk profiles. At-home use eliminates the supervised setting that is a key safety feature of in-office treatment, raising concerns about misuse, unsupervised adverse effects, and variable absorption. The evidence base for at-home ketamine formulations is less robust than for IV infusions or Spravato.

Geographic and equity considerations:

Ketamine clinics are disproportionately located in urban areas and affluent communities. Rural patients, uninsured individuals, and historically marginalized populations face significant access barriers. This is an ongoing equity concern that the field has yet to adequately address.

Ketamine and esketamine are typically considered after other treatments have been tried, and they are not appropriate for everyone. Several evidence-based alternatives exist for treatment-resistant depression and related conditions:

• Electroconvulsive therapy (ECT): ECT remains the gold standard for severe, treatment-resistant depression. It involves brief electrical stimulation of the brain under general anesthesia and has response rates of approximately 50–70% in treatment-resistant populations. Despite persistent stigma, modern ECT is safe and well-tolerated, though it can cause temporary memory difficulties.
• Transcranial magnetic stimulation (TMS): A non-invasive procedure that uses magnetic pulses to stimulate specific brain regions. FDA-cleared for treatment-resistant depression and OCD. It does not require anesthesia and has a favorable side effect profile, though response rates are generally more modest than ECT or ketamine.
• Vagus nerve stimulation (VNS): An implanted device that delivers electrical pulses to the vagus nerve. FDA-approved for treatment-resistant depression, though its effects develop gradually over months.
• Medication optimization: Augmentation strategies — such as adding lithium, atypical antipsychotics (e.g., aripiprazole, quetiapine), or thyroid hormone to an existing antidepressant — have substantial evidence in treatment-resistant depression. A thorough medication review by a psychiatrist is an essential step before pursuing procedural treatments.
• Psychotherapy: Evidence-based psychotherapies such as cognitive behavioral therapy (CBT), behavioral activation, and dialectical behavior therapy (DBT) remain cornerstone treatments. For treatment-resistant depression, intensive psychotherapy formats or combined approaches may offer benefit. Some providers are exploring ketamine-assisted psychotherapy (KAP), which integrates psychotherapy sessions during or shortly after ketamine administration to capitalize on the heightened neuroplasticity window.
• Psilocybin-assisted therapy: In August 2024, the FDA had not yet approved psilocybin, though it has received Breakthrough Therapy designation for treatment-resistant depression. Clinical trials have shown promising results, and it represents a potential future option. Patients should be aware that psilocybin therapy is not yet legally available outside of clinical trials in most U.S. jurisdictions.
• Lifestyle and integrative approaches: Regular aerobic exercise, structured sleep improvement, and dietary modifications have demonstrated antidepressant effects in clinical research. While these are unlikely to be sufficient as standalone treatments for severe, treatment-resistant depression, they are valuable adjuncts to any treatment plan.

The choice among these options should be made collaboratively with a psychiatrist who can weigh the severity of symptoms, treatment history, medical comorbidities, personal preferences, and practical considerations such as cost and access.

If you are experiencing persistent depressive symptoms that have not improved with standard treatments, or if you are experiencing thoughts of suicide or self-harm, it is important to seek professional evaluation promptly.

Consider discussing ketamine or esketamine with a psychiatrist if:

• You have been diagnosed with major depressive disorder and have not responded adequately to two or more antidepressant trials.
• You are experiencing severe depressive symptoms with suicidal ideation and need rapid symptom relief while longer-term treatments take effect.
• Other treatment-resistant depression interventions (such as ECT or TMS) have been considered, and your provider believes ketamine may be appropriate in your case.

Crisis resources:

• 988 Suicide and Crisis Lifeline: Call or text 988 (available 24/7 in the United States).
• Crisis Text Line: Text HOME to 741741.
• If you are in immediate danger, call 911 or go to your nearest emergency department.

Ketamine and esketamine represent a genuine advance in the treatment of severe depression — but they are most effective when integrated into a comprehensive treatment plan that includes psychiatric care, psychotherapy, and attention to overall well-being. No single treatment works for everyone, and finding the right approach often requires patience, persistence, and professional guidance.