Esketamine nasal spray is prescribed at three fixed dose levels: 28 mg, 56 mg, and 84 mg per session. Most adults start at 56 mg and may be titrated up to 84 mg based on how well they respond and how they tolerate the drug, while older adults typically begin at 28 mg. The dosing schedule changes as treatment progresses, shifting from twice-weekly sessions during the first month to weekly or every-other-week sessions during maintenance. Getting these details right matters more than usual because every dose is administered under medical supervision in a certified healthcare setting, so both patients and clinicians benefit from knowing what to expect.
The Three Dose Levels and Who Gets What
Esketamine nasal spray (brand name Spravato) comes in single-use devices that each deliver 28 mg. A 56 mg session means two devices, and an 84 mg session means three, with a five-minute gap between each device. For adults under 65 with treatment-resistant depression, treatment generally begins at 56 mg and can be increased to 84 mg at subsequent sessions if the response is insufficient. Adults 65 and older start at 28 mg for the first two sessions, with the option to increase to 56 mg or 84 mg based on tolerability and clinical response.1The American Journal of Geriatric Psychiatry. Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression This lower starting point for older patients is a precaution against side effects like dizziness and blood pressure increases, not a reflection of reduced efficacy; post-hoc analyses suggest older and younger adults experience similar depression improvement on esketamine.2PubMed. Comparison of Long-Term Efficacy and Safety of Esketamine Nasal Spray Plus Oral Antidepressant in Younger Versus Older Patients With Treatment-Resistant Depression
The drug is always paired with a newly started or ongoing oral antidepressant. Esketamine was not designed as a standalone treatment in most approved indications; the pivotal trials tested it as add-on therapy. Patients in the registration studies received esketamine nasal spray at 56 or 84 mg twice weekly alongside a new oral antidepressant, with the esketamine dose flexibly adjusted based on response.3PubMed. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression A recent trial did evaluate esketamine as monotherapy and found that both 56 mg and 84 mg produced significantly greater improvement than placebo by day 28, with effect sizes of roughly 0.48 and 0.63, respectively.4JAMA Psychiatry. Esketamine Monotherapy in Adults With Treatment-Resistant Depression That finding suggests the drug has antidepressant properties on its own, but monotherapy is not yet how it is typically prescribed.
The Treatment Schedule and How It Shifts Over Time
Esketamine dosing follows a phased calendar. During the induction phase, which lasts four weeks, sessions happen twice a week. The goal is to load the therapeutic benefit quickly. After induction, the frequency drops: during weeks five through eight, sessions typically move to once a week. From week nine onward, the schedule can thin further to once every two weeks, depending on how the patient is doing.
The decision about how often to continue sessions is guided by symptom scores. In the phase 3 maintenance trials, clinicians evaluated patients every four weeks using a standardized depression rating scale. If the patient was in remission, session frequency was reduced or held at every other week. If depressive symptoms were still present, frequency stayed at weekly or was increased back to weekly from every other week.5PubMed Central. Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data The guiding principle is to find the lowest frequency that keeps the patient well. This approach balances the real-world burden of in-clinic dosing against the risk of relapse.
That risk of relapse is not trivial. In a randomized withdrawal study, patients who had achieved stable remission on esketamine plus an oral antidepressant and then switched to placebo nasal spray relapsed at nearly twice the rate of those who continued esketamine. Continuing the drug cut relapse risk by about half for those in stable remission and by about 70% for those who had reached stable response but not full remission.6PubMed Central. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression These numbers make a strong case for ongoing maintenance rather than stopping after the induction phase, even when the patient feels significantly better.
Why Higher Doses Tend to Work Better
A meta-analysis pooling data from 12 studies found that intranasal esketamine at 56 to 84 mg outperformed the 28 mg dose for reducing depression symptoms.7PubMed. Efficacy of Intravenous Ketamine and Intranasal Esketamine With Dose Escalation for Major Depression The monotherapy trial mentioned earlier reinforced this, showing a clear dose-response pattern: the 84 mg group improved more than the 56 mg group, and both improved more than placebo, with improvement detectable as early as 24 hours after the first dose.8JAMA Psychiatry. Esketamine Monotherapy in Adults With Treatment-Resistant Depression
This dose-response gradient is part of why the 28 mg dose exists mainly as a gentler entry point for older adults rather than a target therapeutic dose for younger patients. For most adults under 65, the clinical logic is to start at 56 mg and move to 84 mg if the initial response is underwhelming, rather than staying at the lower dose.
One complication is body weight. The nasal spray uses fixed doses, meaning a 56 mg dose represents a very different drug exposure for someone who weighs 60 kg versus someone who weighs 120 kg. Some researchers have flagged that the current fixed-dose approach may be insufficient for people with obesity, since the drug-per-kilogram ratio drops substantially at higher body weights.9PubMed Central. Key Considerations for the Use of Ketamine and Esketamine for the Treatment of Depression – Section: Expert opinion The intranasal bioavailability of the drug runs around 50 to 54% of the total dose delivered, so even the 84 mg spray is delivering roughly 43 to 45 mg of active drug to the bloodstream.10PubMed. Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression – Section: Results For a larger individual, that may fall short of the per-kilogram exposure achieved in clinical trials, which enrolled participants of widely varying sizes but reported results only at fixed dose levels.
Liver Function and Dose Adjustments
Esketamine is metabolized in the liver, and impaired liver function changes how the drug is handled. In patients with moderate hepatic impairment, the drug’s blood levels roughly doubled compared to patients with normal liver function, and the half-life extended from about 16.5 hours to about 18.7 hours.11Janssen Medical Information. SPRAVATO – Hepatic Adverse Events and Use in Patients with Hepatic Impairment Despite these pharmacokinetic changes, the manufacturer’s labeling does not specify formal dose reductions for mild or moderate impairment. Instead, the guidance is to monitor these patients for a longer period after each dose, since the drug and its side effects may linger.12Psychopharmacology Institute. Esketamine Guide: Pharmacology, Indications, Dosing Guidelines and Adverse Effects – Section: Hepatic impairment
For severe hepatic impairment, the situation is simpler: the drug has not been studied in that population, and use is not recommended. This is a hard stop in the labeling, not a suggestion to proceed with caution.
What Happens During a Dosing Session
Because esketamine can cause dissociation, sedation, and temporary blood pressure spikes, every dose is given in a certified healthcare setting under direct observation. You cannot take the nasal spray home. A typical session involves arriving at the clinic, self-administering the spray under supervision, and then being monitored for at least two hours. During that window, clinicians check blood pressure and assess for dissociative or sedating effects. Most patients are cleared to leave after the monitoring period, though they should not drive, operate heavy machinery, or make important decisions for the rest of the day.
The blood pressure response is worth understanding. Esketamine tends to raise both systolic and diastolic blood pressure, with the peak occurring about 40 minutes after dosing and typically resolving within two hours. A study of subcutaneous esketamine (a different route, but informative about the drug’s general cardiovascular effects) found no significant difference in blood pressure elevation across a range of doses.13PubMed. Effects of Subcutaneous Esketamine on Blood Pressure and Heart Rate in Treatment-Resistant Depression – Section: Results In other words, the blood pressure bump is more about the drug being present at all than about how much you took. People with uncontrolled hypertension or a history of aneurysmal vascular disease are generally excluded from treatment for this reason.
Older Adults and How Their Experience Differs
The age-related dosing difference is one of the more visible features of esketamine prescribing. Beyond the lower starting dose, do older patients actually experience different side effects? Data from a long-term safety study showed largely comparable profiles between younger and older adults. Rates of treatment-related adverse events during the induction phase were about 86% in younger patients versus 75% in older patients, and the rates of serious events were low and similar in both groups. Blood pressure increases occurred at similar frequencies, though slightly more older adults experienced elevated blood pressure during the maintenance phase. Falls were uncommon in both groups, though marginally more frequent in older patients. Cognitive testing did not show meaningful differences between age groups.14PubMed. Comparison of Long-Term Efficacy and Safety of Esketamine Nasal Spray Plus Oral Antidepressant in Younger Versus Older Patients With Treatment-Resistant Depression
In a separate trial focused specifically on elderly patients with treatment-resistant depression, the most common side effects were dizziness, nausea, headache, fatigue, blood pressure increases, and dissociation.15The American Journal of Geriatric Psychiatry. Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression These are the same side effects seen in younger patients; they just require more caution in a population more likely to have cardiovascular concerns or fall risk.
Adolescents and the Emerging Pediatric Evidence
Esketamine is not yet approved for adolescents, but research in this group is underway. A phase 2b study enrolled 147 adolescents aged 12 to 17 who had major depressive disorder with imminent suicide risk. Participants received esketamine at 28, 56, or 84 mg, or a comparator drug, twice weekly for four weeks. The pooled higher doses (56 and 84 mg) showed a statistically significant reduction in depression scores at 24 hours after the first dose compared to the comparator. The most frequently reported adverse events, occurring in more than 20% of participants, were dizziness, nausea, dissociation, headache, taste changes, sleepiness, vomiting, numbness, and intentional self-injury.16PubMed. Effect of Esketamine on Depressive Symptoms in Adolescents With Major Depressive Disorder at Imminent Suicide Risk
The inclusion of intentional self-injury among the adverse events is striking and reflects the extremely high-risk population enrolled in this study rather than a direct pharmacological effect of esketamine. These were adolescents already at imminent risk of suicide. Still, it underscores why pediatric dosing and monitoring protocols will be scrutinized carefully before any regulatory expansion to younger populations.
Does Taking Benzodiazepines Change the Dose Equation
Many patients with treatment-resistant depression also take benzodiazepines for anxiety or insomnia, which creates a practical dosing question: does concurrent benzodiazepine use blunt esketamine’s antidepressant effect or worsen its side effects? The evidence is mixed and somewhat conflicting. A pooled analysis of randomized trials focused on patients with acute suicidal ideation found no significant difference in depression score improvement between esketamine-treated patients who were also taking benzodiazepines and those who were not.17PubMed Central. Effect of Concomitant Benzodiazepine Use on Efficacy and Safety of Esketamine Nasal Spray in Patients with Major Depressive Disorder and Acute Suicidal Ideation or Behavior
However, a more recent observational study of subcutaneous esketamine found that benzodiazepine users had higher depression scores throughout treatment, suggesting a possible dampening of the antidepressant response.18PubMed. Role of Concomitant Benzodiazepines, Lithium, and Lamotrigine in Modulating the Antidepressant Effects of Subcutaneous Esketamine in Patients With Treatment-Resistant Depressive Episodes These were different routes of administration and different study designs, so the disagreement is not cleanly resolved. The practical takeaway is that benzodiazepines are not a contraindication to esketamine, but clinicians may want to consider whether benzodiazepine tapering is feasible, especially if the esketamine response seems suboptimal.
Alternative Routes and How Their Dosing Differs
The approved nasal spray is by far the most common formulation, but researchers have explored other routes that carry very different dosing math. Oral esketamine has lower bioavailability because the drug undergoes extensive first-pass metabolism in the liver before reaching the bloodstream. A pilot study of oral esketamine used 1.25 mg/kg daily for 21 consecutive days in patients with severe treatment-resistant depression.19PubMed Central. Repeated, Low-Dose Oral Esketamine in Patients With Treatment-Resistant Depression: Pilot Study That is a weight-based dose, in contrast to the fixed doses used for the nasal spray.
A larger double-blind trial tested fixed low-dose oral esketamine at 30 mg three times daily for six weeks and found no benefit over placebo. A subsequent open-label phase of the same study used individually titrated doses ranging from 0.5 to 3.0 mg/kg twice weekly and suggested possible antidepressant effects at those higher, personalized doses.20Molecular Psychiatry. Oral Esketamine in Patients With Treatment-Resistant Depression: A Double-Blind, Randomized, Placebo-Controlled Trial With Open-Label Extension The lesson from oral dosing research so far is that a flat low dose taken daily does not seem to work, while individually adjusted higher doses might, but the evidence is still too thin to support clinical adoption. The nasal route remains preferred precisely because it bypasses the liver’s first pass, delivering a more predictable and substantially higher proportion of each dose to the brain.
How Esketamine’s Mechanism Connects to Its Dosing Logic
Esketamine works by blocking a specific type of receptor in the brain involved in glutamate signaling, the NMDA receptor. Its activity is thought to be preferentially directed at a particular subtype of this receptor, which distinguishes it from racemic ketamine’s broader binding profile.21Taylor & Francis Online (Expert Opinion on Therapeutic Targets). Modulating Tonic NMDA Receptor Currents: Mechanistic Insights Into Ketamine, Esketamine, and Dextromethorphan for Major Depressive Disorder – Section: Expert Opinion This receptor blockade triggers a downstream cascade that promotes new synaptic connections, which is thought to underlie the rapid antidepressant effects seen within hours of the first dose.
The dosing regimen reflects this mechanism in a few ways. The twice-weekly induction schedule aims to establish the synaptic changes early and quickly. The taper to weekly and then every-other-week dosing during maintenance is based on the idea that once those connections are established, they can be maintained with less frequent stimulation. The rapid onset of action also explains why treatment response is evaluated after just four weeks of induction rather than the six to eight weeks typical for oral antidepressants.
Practical Realities That Affect Dosing Decisions
Beyond the pharmacology, several real-world factors shape how dosing plays out. Nasal congestion, for instance, can reduce drug absorption. Patients are typically advised to use a nasal decongestant at least an hour before their session if they have a cold or allergies. Blowing the nose or sniffing forcefully immediately after spraying can also reduce how much drug reaches the nasal lining. The technique matters: the spray goes into one nostril, the patient rests for five minutes, then the second device goes into the other nostril. For a three-device session (84 mg), this alternating pattern continues with a third spray.
The requirement for in-clinic dosing creates its own constraints. Each session occupies roughly two and a half to three hours of the patient’s day, including travel, dosing, and the post-dose monitoring period. During induction, that means two half-day commitments per week for a month. Some patients find this schedule manageable; others struggle with it, particularly those with jobs that are difficult to leave or those who live far from a certified treatment center. In some cases, these logistical barriers become the dominant factor in how long treatment continues, more so than the pharmacology. Clinicians sometimes face the decision of whether a slightly suboptimal frequency dictated by the patient’s schedule is better than no esketamine at all.
Insurance coverage adds another layer. Not all insurers cover every approved dose or session frequency, and prior authorization requirements can delay the start of treatment or interrupt the schedule during maintenance. The cost per session for the drug alone runs into the hundreds of dollars, and the required medical supervision adds to the total. These financial pressures occasionally lead to conversations about moving to every-other-week dosing sooner than the clinical evidence alone might suggest, though doing so prematurely could increase relapse risk as the maintenance trial data demonstrated.