Esketamine (Spravato): Dosing, Monitoring, Side Effects & REMS

What It's Used For

Esketamine (Spravato) is a clinic-only intranasal antidepressant used when depression is severe and standard medications haven’t been enough, or when there are active suicidal thoughts or behavior.

Primary Indications

Treatment-Resistant Depression (TRD): For adults who have not responded adequately to at least 2 different antidepressant trials, used as monotherapy or together with an oral antidepressant.Major Depressive Disorder with Suicidal Ideation or Behavior: For adults with severe depression plus suicidal thoughts or actions, always given with an oral antidepressant to rapidly reduce depressive symptoms.Rapid symptom relief setting: When weeks of waiting for a typical antidepressant is not acceptable because of severity, functional decline, or suicidality.Structured clinic-based treatment: Only administered in certified health care settings with on-site monitoring and no take-home doses.

How Fast It Works

Esketamine works on a much faster timeline than typical antidepressants, but the intense effects are short-lived and require monitoring.

20–40 minutes

Peak blood levels; dissociation, dizziness, and sedation often begin and peak in this window.

1–2 hours

Most dissociative and perceptual changes fade; patients are usually coming back to baseline but still monitored.

Up to ~4 hours

Blood pressure effects gradually settle; this is why the observation period is at least 2 hours after dosing.

Hours to days

Many patients notice some mood shift or reduced intensity of suicidal thinking in this timeframe.

Weeks

Ongoing sessions (induction, then maintenance) are used to sustain antidepressant effects.

Safe Discontinuation

Esketamine is not a daily home medication; it’s a clinic-based series of treatments. There isn’t a classic ‘taper’ like with SSRIs or benzodiazepines, but you still don’t want to stop abruptly in someone who is unstable.

Key Points

Treatment model: Esketamine is typically given twice weekly for 4 weeks (induction), then once weekly, and possibly every 2 weeks (maintenance). Frequency, not dose, is usually the main variable over time.
Stopping after induction: If there is no meaningful benefit after 4 weeks, treatment is usually discontinued and the focus shifts to other strategies (medication changes, psychotherapy, neuromodulation).
Stepping down frequency: For responders, the maintenance phase may gradually space out sessions (eg, weekly → every 2 weeks) while monitoring for return of depressive symptoms.
Relapse management: If symptoms flare after spacing out sessions, clinicians may temporarily increase session frequency back to weekly or twice weekly rather than abruptly discontinuing.
Physiologic withdrawal: There is no well-defined esketamine ‘withdrawal syndrome’ like with benzodiazepines, but abrupt discontinuation can be associated with depression relapse or return of suicidality. Ongoing monitoring and support remain essential.

Dosing Information

Adult Dosing

trd induction: 56 mg or 84 mg intranasally twice weekly for 4 weeks. Dose is chosen and adjusted based on response and tolerability. Reassess at the end of week 4 to determine whether to continue.

trd maintenance: Beginning week 5, continue the effective dose (56 mg or 84 mg) once weekly. Starting at week 9, maintain once weekly or reduce to every 2 weeks based on symptom control and functioning.

mdd suicidality induction: 84 mg intranasally twice weekly for 4 weeks, given together with an oral antidepressant. Dose may be reduced to 56 mg twice weekly if not tolerated. Use beyond 4 weeks in this indication has not been established.

missed sessions: If a treatment session is missed and symptoms have not worsened, resume the current schedule at the next visit. If a maintenance session is missed and symptoms worsen, consider returning to the previous, more frequent schedule (eg, every 2 weeks → weekly or weekly → twice weekly).

setting and monitoring: Administer only in a REMS-certified health care setting under direct supervision. Monitor for sedation, dissociation, blood pressure changes, and respiratory status for at least 2 hours after dosing, and only discharge once clinically stable.

elderly: Consider lower starting doses (eg, 28–84 mg intranasally twice weekly for 4 weeks) with cautious titration and extended monitoring, given higher exposure and greater vulnerability to blood pressure changes and sedation.

hepatic: No specific dose adjustment recommended for mild to moderate hepatic impairment (Child-Pugh A or B), but exposure is increased—monitor for a longer period after dosing. Use is not recommended in severe hepatic impairment (Child-Pugh C).

renal: No dosage adjustment is generally needed; <1% of the dose is excreted unchanged in urine, but clinical judgment should guide use in advanced kidney disease.

Simple Explanation

For most people, Spravato starts with twice-weekly sessions for a month. If it helps, the clinic usually backs off to once a week, and sometimes every other week. You don’t adjust it at home—each dose is given and monitored by clinic staff using 2–3 nasal spray devices per session.

Available Formulations

Intranasal Solution Therapy Pack (US): Spravato 56 mg dose—two 28 mg nasal spray devices (each device contains 2 sprays, 1 in each nostril).
Intranasal Solution Therapy Pack (US): Spravato 84 mg dose—three 28 mg nasal spray devices (each device contains 2 sprays, 1 in each nostril).
Intranasal Solution Therapy Pack (Canada): Spravato 28 mg device (2 sprays per device).
Each device is single-use, unprimed, and must be discarded according to Schedule III controlled-substance procedures after use. No generic equivalent is currently available.

Critical Safety Information

Esketamine can cause significant sedation, dissociation, blood pressure spikes, and respiratory depression. It is only available through a REMS program and must be given in a certified clinic with at least 2 hours of monitoring after each dose.

→You will receive Spravato only in a certified clinic. Plan to be there for several hours and arrange a ride home—no driving the day of treatment.
→Expect possible dissociation (feeling detached or ‘out of body’), dizziness, and sedation. These usually peak in the first hour and improve over time.
→Your blood pressure and breathing will be checked before and after each dose. Tell staff right away if you feel chest pain, shortness of breath, severe headache, or vision changes.
→Spravato has abuse potential. Be open with your clinician about any history of substance use, cravings, or urges to misuse ketamine or other drugs.
→Even if you feel better quickly, keep safety planning in place. Esketamine has not been proven to prevent suicide, and you still need ongoing therapy, medication management, and follow-up.
→If you are pregnant, planning pregnancy, or breastfeeding, talk with your prescriber before starting or continuing Spravato so you can weigh risks and benefits together.

Side Effects

Most people feel sedated, dizzy, and somewhat disconnected for a few hours after treatment. Blood pressure goes up for a while, and nausea is common. Serious risks include respiratory depression, psychiatric activation, and rare cardiovascular events.

Common Things People Notice

Feeling ‘out of body’ or disconnected (dissociation)
Sedation, drowsiness, or feeling very tired
Dizziness, vertigo, or feeling unsteady
Nausea and sometimes vomiting
Headache
Temporary increases in blood pressure
Anxiety, restlessness, or feeling wired
Trouble concentrating or slowed thinking
Throat irritation or strange taste after nasal spray

Common Side Effects

≈28%

Dissociation (depersonalization, derealization, altered perception)— You may feel like you’re watching yourself from the outside, like time is distorted, or the room feels unreal. This typically starts within 20–40 minutes, peaks during the first hour, and improves by around 1–2 hours. Staff should explain this ahead of time and stay with you if it feels uncomfortable.

≈22%

Dizziness and Vertigo— Feeling woozy, off-balance, or like the room is spinning is common. You’ll be monitored in a safe setting and helped when you stand up or walk. This is a big part of why you can’t drive yourself home.

Nausea ≈25%; vomiting ≈7%

Nausea and Vomiting— Nausea can feel like mild motion sickness. Avoiding food for 2 hours and liquids for 30 minutes before treatment helps. Let staff know if nausea is an issue—anti-nausea medications can be considered.

Sedated state ≈6%; lethargy ≈7%; intoxicated feeling ≈7%

Sedation, Lethargy, ‘Intoxicated’ Feeling— Many people describe this as feeling drunk, drugged, or heavy. Thinking may feel slower, and tasks take more effort. You’ll need to rest in the clinic and then take it easy the rest of the day.

≈19%

Headache— Headaches can occur during or after sessions. Hydration, rest, and simple pain relievers (if approved by your prescriber) usually help.

Increased blood pressure ≈5% (clinically significant increases may be higher in real-world use)

Blood Pressure Elevation— Your blood pressure will be checked before and after each dose. You might notice flushing, pressure in your head, or pounding heartbeat. The team is there to manage this and will refer you to emergency care if concerning symptoms appear.

Insomnia ≈5%; attention disturbance ≈2%; hypoesthesia (numbness) ≈4%

Sleep and Cognitive Changes— Some people feel mentally slowed for a few hours and then wired or unable to sleep that night. Others feel calmer and sleepier. Short-term cognitive testing has generally returned to baseline by 2–4 hours, but long-term ketamine misuse is linked to cognitive problems.

Throat irritation ≈4%

Throat or Nasal Discomfort— Mild burning, irritation, or an odd taste in the back of your throat is fairly common and usually brief.

Serious side effects

Slowed breathing: slow or shallow breathing, lower oxygen levels, or being hard to wake. This is why you are watched continuously, with a finger clip that checks your oxygen (pulse oximetry), for at least 2 hours.
Hypertensive crisis or hypertensive encephalopathy: Severe blood pressure elevation with chest pain, shortness of breath, severe headache, visual changes, seizures, confusion, or focal neurologic deficits. Requires emergency evaluation.
Cardiovascular events: Postmarketing reports include bradycardia and hypotension, particularly in vulnerable patients.
Psychiatric activation: Panic attacks, agitation, mania/hypomania, paranoia, or worsening depression have been described. Any sudden behavior change during or after treatment should be taken seriously.
Abuse, dependence, and misuse: Drug abuse has been reported; risk is higher in people with substance use histories or when supervision is inadequate.
Bladder and urinary symptoms: Frequent urination, urgency, discomfort, or cystitis-like symptoms warrant evaluation, especially with longer-term treatment.
Suicidal thoughts or behavior: Like all antidepressants, esketamine can be associated with emergent or worsening suicidality, especially early in treatment or during dose changes.

Critical Drug Interactions

Esketamine is metabolized mainly by CYP2B6 and CYP3A4 and acts as a CNS depressant. The biggest concerns are combinations that further depress the brain, raise blood pressure, or alter its metabolism.

With: Other CNS Depressants (benzodiazepines, alcohol, opioids, sedative-hypnotics, gabapentinoids)

Risk: Additive or synergistic sedation and respiratory depression; greater risk of impaired consciousness and accidents.

Action: Use the lowest effective doses when combinations are unavoidable. Monitor closely for excessive sedation and respiratory compromise during and after esketamine sessions. Absolutely no alcohol on treatment days.

With: Psychostimulants (eg, amphetamine formulations, methylphenidate) and MAOIs

Risk: Additive increases in blood pressure and heart rate; higher risk for hypertensive events.

Action: Carefully assess cardiovascular risk before combining. Monitor blood pressure more frequently around the time of esketamine dosing and consider dose or schedule adjustments.

With: Drugs Affecting CYP2B6 or CYP3A4 (eg, certain azoles, macrolides, some anticonvulsants)

Risk: Theoretical risk of altered esketamine or metabolite levels (either increased side effects or reduced efficacy).

Action: Review medication list for strong inducers or inhibitors. Adjust monitoring accordingly and consider alternative agents when feasible.

With: Other Dissociative or Hallucinogenic Agents (ketamine, PCP, high-dose dextromethorphan, recreational psychedelics)

Risk: Increased dissociation, perceptual disturbances, and psychiatric destabilization.

Action: Avoid co-use. Screen for recreational substance use and counsel patients to avoid non-prescribed psychoactive substances, particularly around treatment days.

With: Uncontrolled Hypertension or Significant Cardiovascular/Cerebrovascular Disease

Risk: Although not a classic ‘drug–drug’ interaction, underlying vascular disease greatly amplifies risk of dangerous blood pressure rises or neurologic events.

Action: Thorough cardiovascular review before initiation. If baseline BP is >140/90 mm Hg, weigh risks and benefits of delaying treatment and involve primary care or cardiology as needed.

Pregnancy, Breastfeeding, Special Groups

Esketamine is used in complex, high-risk situations. Pregnancy, breastfeeding, older age, liver disease, and substance use history all change the risk–benefit conversation.

👶Pregnancy

Esketamine crosses the placenta, and animal data raise concerns about potential effects on brain development with NMDA-blocking drugs. Human data on intranasal esketamine in pregnancy are limited. At the same time, untreated severe depression is clearly associated with preterm birth, low birth weight, preeclampsia, postpartum depression, and long-term impacts on attachment. Decisions about use in pregnancy should involve shared decision making, weighing severity of maternal illness, response to other treatments, and timing in pregnancy. Use the lowest effective dose, avoid unnecessary polypharmacy, and monitor mood monthly with validated tools.

🤱Breastfeeding

Esketamine is present in breast milk. Based on animal data, NMDA-blocking and GABA-potentiating drugs may affect brain development, especially in the first months to years of life. The manufacturer does not recommend breastfeeding during esketamine treatment. If a patient is stable on esketamine and strongly wishes to breastfeed, risk–benefit discussion is essential, considering infant age, maternal relapse risk, and alternative options.

👧Children & Adolescents (Under 18)

Esketamine is not approved for children or teens. Antidepressants in general raise the risk of suicidal thoughts and behavior in children and teens; esketamine should not be used in this group outside of research studies.

👴Older Adults (65+)

Older adults have higher esketamine exposure (Cmax and AUC) and are more vulnerable to blood pressure spikes, sedation, falls, and cognitive effects. Start low, go slow, monitor closely, and reassess frequently whether benefits continue to outweigh risks.

🔬Liver Impairment

With moderate liver problems, esketamine reaches higher levels and stays in your body longer, so you may need to be watched longer after each dose. It is not recommended with severe liver problems (Child-Pugh C).

💧Kidney Impairment

Because very little esketamine is excreted unchanged in urine, dose adjustment is generally not required; however, comorbidities and overall medical fragility in advanced kidney disease still warrant caution and close monitoring.

Clinical Monitoring

Observation: you stay in a health care setting for at least 2 hours after each dose, and longer if sleepiness, feeling detached (dissociation) or blood pressure changes don't settle.
Respiratory status: Check respiratory rate, level of consciousness, and oxygen saturation (pulse oximetry) during and after treatment. Watch for respiratory depression, particularly in patients on other CNS depressants.
Blood pressure and heart rate: Measure BP before dosing. If BP is >140/90 mm Hg, consider risks and benefits of proceeding. Recheck around 40 minutes post-dose and periodically for at least 2 hours or until values trend down.
Suicidal ideation and behavior: Closely monitor for changes in suicidal thoughts, intent, or behavior, especially early in treatment, during dosing frequency changes, and after missed treatments.
Abuse and misuse: Before starting, assess history of substance use or addiction. During treatment, monitor for craving, drug-seeking behavior, or non-prescribed ketamine use.
Psychiatric symptoms: Track mood, anxiety, panic, mania/hypomania, psychotic symptoms, and overall functioning across visits. Watch for emergent agitation, paranoia, or marked behavior changes.
Cognitive effects: Note short-term cognitive changes during sessions. Ask about memory, attention, and executive function over time, especially in older adults or those with prior cognitive issues.
Urinary and bladder symptoms: Monitor for urinary frequency, urgency, pain, or cystitis-like symptoms. Refer for evaluation if persistent or severe.
Cardiovascular and cerebrovascular risk review: Prior to initiation, assess for aneurysms, arteriovenous malformations, prior intracerebral hemorrhage, recent MI or stroke, and uncontrolled hypertension.
Reproductive status: For patients who could become pregnant, consider pregnancy testing before starting and periodically as clinically indicated, and document contraceptive and reproductive plans.

How Well It Works

Meaningful symptom improvement in treatment-resistant depression within 4 weeks

Roughly 50–70% of patients respond

vs Higher and faster response rates than oral antidepressant plus placebo nasal spray in registration trials.

Esketamine stands out for speed: many patients notice some shift in depressive symptoms or suicidal intensity within days, sometimes within 24 hours. It does not work for everyone, and it is not a cure, but in people who have already failed multiple antidepressants, adding or using esketamine can significantly increase the odds of getting at least partial relief.

Mechanism of Action

Esketamine is the S-enantiomer of racemic ketamine and acts as a noncompetitive NMDA receptor antagonist. In simpler terms, it rapidly changes how glutamate (a major excitatory brain chemical) is released and processed. This ‘jolt’ to the glutamate system appears to increase synaptic connectivity and plasticity in mood-related brain circuits, which may explain why some people feel better within hours to days rather than weeks. The main circulating metabolite, noresketamine, also has activity at NMDA receptors but with lower affinity. The exact mechanism of its antidepressant effect is still not fully understood.

Place in Treatment Algorithm

Esketamine sits fairly late in the depression treatment algorithm, reserved for high-risk and hard-to-treat situations. For most patients, first-line treatments are still SSRIs or SNRIs, psychotherapy, lifestyle interventions, and sometimes augmentation strategies with atypical antipsychotics or mood stabilizers. Esketamine becomes relevant when one of two things is true: (1) multiple antidepressant trials have failed (treatment-resistant depression), or (2) the depression is severe with suicidal ideation or behavior and you need something that works faster than traditional options. It is not a standalone cure—patients remain on oral antidepressants, continue therapy, and still need robust safety planning. Because of REMS restrictions, it also requires access to a certified clinic, time for monitored visits, and careful shared decision making about cost, logistics, and long-term strategy.

Questions people ask

What is Spravato (esketamine) actually used for?

Spravato is an intranasal form of ketamine’s active isomer, approved for adults with treatment-resistant depression and for adults with major depressive disorder who have suicidal thoughts or behavior. It’s used when standard antidepressants haven’t been enough or when waiting weeks for response is too risky. It’s always given in a clinic under supervision, never as a take-home spray.

How is Spravato different from a regular antidepressant pill?

Traditional antidepressants mainly work on serotonin, norepinephrine, or dopamine and can take 4 to 8 weeks to show full benefit. Spravato targets the glutamate system through NMDA receptor blockade and often acts within hours to days. It’s not taken daily at home; instead, you receive it in a clinic 1–2 times per week, with at least 2 hours of monitoring after each dose. You usually continue your oral antidepressant alongside Spravato.

How fast will I feel better with Spravato?

Many people notice some shift in mood or suicidal intensity within the first few treatments, sometimes within 24 hours. For others it’s more gradual over the first 2–4 weeks. Some people unfortunately don’t respond at all. Your clinician will reassess after the 4-week induction phase to decide if it’s worth continuing.

Why do I have to stay for 2 hours after each treatment?

Spravato can cause sedation, dissociation, blood pressure spikes, and, in rare cases, breathing problems. These effects are most intense during the first couple of hours. Staying in the clinic for at least 2 hours lets staff monitor your vital signs and mental status, help you if you feel unsteady or distressed, and decide when it’s safe for you to leave.

Can I drive after taking Spravato?

No. You should not drive, operate machinery, or do anything that requires full alertness until the next day after a full night’s sleep. You must arrange for a trusted person or service to drive you home after every session. This is a firm safety requirement, not a suggestion.

Is Spravato the same as IV ketamine therapy?

They are related but not identical. Spravato is esketamine (one half of the ketamine molecule) delivered via nasal spray at FDA-approved doses and schedules, with a formal REMS program and insurance pathways. IV ketamine is typically racemic ketamine, given off-label at varying doses and protocols depending on the clinic. Risk profiles, monitoring practices, and evidence bases overlap but are not the same.

Can Spravato make my depression or anxiety worse?

Sometimes. While many people feel better, others can experience intense anxiety, panic, agitation, or even worsening depression or suicidal thoughts, particularly early on. That’s why your mood, behavior, and safety plan are closely monitored throughout treatment. If you or your family notice sudden behavior changes, more intense suicidal thinking, or manic symptoms, contact your clinician or emergency services immediately.

Is Spravato addictive?

Esketamine can be misused, especially because it is related to ketamine, which is used recreationally. The REMS safety program, getting each dose in the clinic, and having no take-home doses lower that risk, but do not remove it. The risk is higher if you have a history of substance use or addiction. Expect your prescriber to ask about substance use, talk openly with you about any cravings or urges, and watch for signs of misuse.

Will Spravato stop me from attempting suicide?

Spravato can rapidly reduce depressive symptoms and the intensity of suicidal thoughts, but it has not been proven to prevent suicide or stop all suicide attempts. Think of it as one tool in a larger safety plan that includes close follow-up, therapy, crisis resources, family or support involvement, and ongoing medication management. Even if you feel dramatically better, it’s important to keep your safety net in place.

What side effects should I expect during a session?

Most people experience some combination of feeling spacey or detached, dizziness, drowsiness, and changes in perception (sounds, time, and surroundings may feel different). Nausea, headache, and a sense of being ‘intoxicated’ are common. Blood pressure usually goes up for a bit. These effects mostly peak in the first hour and improve as your body clears the drug, which is why monitoring is focused on that window.

Can I use Spravato if I’m pregnant or breastfeeding?

Data in pregnancy and breastfeeding are limited, and there are theoretical concerns about brain development in the fetus or infant. At the same time, untreated severe depression and suicidality carry serious risks, including for pregnancy outcomes. If you are pregnant, planning pregnancy, or breastfeeding, your clinician will walk through the risks and benefits with you. Decisions are highly individualized and should involve shared decision making rather than automatic yes or no answers.

If Spravato works for me, do I have to stay on it forever?

Not necessarily. Many people complete the 4-week induction and then move into a maintenance phase with weekly or every-other-week sessions if they’re still benefiting. Over time, if your mood is stable and you’re doing well on other treatments (like oral antidepressants and therapy), your clinician may gradually space out or discontinue Spravato. The goal is not to keep you in the chair forever—it’s to use this tool strategically as part of a broader, long-term plan.