Esketamine (Spravato)

Number: 0950



Aetna considers esketamine (Spravato) nasal spray medically necessary for the treatment of treatment-resistant depression (TRD) in adults (18 years of age or older) when the following criteria are met:

  • Member has a confirmed diagnosis of severe major depressive disorder (single or recurrent episode), documented by standardized rating scales that reliably measure depressive symptoms (e.g., Beck Depression Scale [BDI], Hamilton Depression Rating Scale [HDRS], Montgomery-Asberg Depression Rating Scale [MADRS], etc.); and
  • Diagnosis is verified by a psychiatrist; and
  • Member does not have a current or recent history (i.e., within the last 6 months) of moderate or severe substance or alcohol use disorder; and
  • Member meets either of the following criteria:
    • Member has experienced inadequate response during the current depressive episode with:
      • Two antidepressants from at least 2 different classes having different mechanisms of actionFootnotes** at the maximally tolerated labeled dose, each used for at least 8 weeks; and
      • Augmentation therapy OR cognitive behavioral therapyFootnotes***; or
    • Member has profound depression and persistent suicidal ideation defined as all of the following:
      • The prescriber represents that, in the absence of the requested drug, within the next 24 to 48 hours the member will require confinement in an acute care psychiatric institution; and
      • Member has a depressive episode so acute and so severe that the member is not able to participate in self-care (e.g., washing, eating), is unable to participate at all in their usual daily activities (e.g., work), and has persistent thoughts of hopelessness and helplessness as well as anhedonia; and
      • Member has thoughts of dying and/or self-harm for at least some part of each and every day; and
  • Esketamine is used in combination with an oral antidepressant (e.g., duloxetine, escitalopram, sertraline, venlafaxine); and
  • Esketamine is administered under the direct supervision of a healthcare provider; and
  • Member will be monitored by a health care provider for at least 2 hours after administration.

Aetna considers continued treatment with esketamine for 3 months medically necessary for members with documented improvement or sustained improvement from baseline in depressive symptoms documented by standardized rating scales that reliably measure depressive symptoms (e.g., Beck Depression Scale [BDI], Hamilton Depression Rating Scale [HDRS], Montgomery-Asberg Depression Rating Scale [MADRS], etc.)

Aetna considers esketamine experimental and investigational for all other indications.

Footnotes*Precertification of esketamine nasal spray is required of all Aetna participating providers and members in applicable plan designs. For precertification of esketamine call (866) 752-7021, or fax (866) 267-3277.

Footnotes** Antidepressant medication classes include:
  1. aminoketones (Wellbutrin/SR/XL [bupropion]);
  2. monoamine oxidase inhibitors (MAOIs) (e.g., Marplan, Nardil, Parnate, phenelzine, tranylcypromine);
  3. noradrenaline and specific serotoninergic antidepressants (NASSAs) (e.g., amoxapine, maprotiline, mirtazapine/ODT, Oleptro ER, Remeron/Solutab, trazodone); 
  4. selective serotonin reuptake inhibitors (SSRIs) (e.g., Celexa, citalopram, escitalopram, fluoxetine, fluvoxamine, Lexapro, Luvox/CR, paroxetine, Paxil/CR, Pexeva, Prozac/Weekly, sertraline, Zoloft);
  5. serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., Cymbalta, desvenlafaxine/ER, duloxetine, Effexor/XR, Fetzima, Irenka, Khedezla, Pristiq, venlafaxine/ER); and
  6. tricyclic antidepressants (TCAs) (e.g., amitriptyline, desipramine, doxepin, Elavil, imipramine, Norpramin, nortriptyline, Pamelor, Surmontil, Tofranil, trimipramine).

Footnotes*** Augmentation therapy is defined as: two antidepressants with different mechanisms of action used concomitantly, an antidepressant and a second-generation antipsychotic used concomitantly, an antidepressant and lithium used concomitantly, an antidepressant and thyroid hormone used concomitantly, or an antidepressant and buspirone used concomitantly.


Major depressive disorder (MDD) has one of the highest morbidities worldwide.  As reported in many clinical trials, standard anti-depressants are effective in only approximately two-thirds of patients. The STAR*D report by Rush et al (2006) compared the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. In the STAR*D trial, adult outpatients with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of <or=5 on the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR(16)) (equivalent to <or=7 on the 17-item Hamilton Rating Scale for Depression [HRSD(17)]) defined remission; a QIDS-SR(16) total score of >or=11 (HRSD(17)>or=14) defined relapse. The QIDS-SR(16) remission rates were similar for the initial and second treatment courses (36.8% and 30.6%, respectively), but were substantially lower for the third and fourth treatment courses (13.7%, and 13.0%, respectively). The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. The study authors concluded that when more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected (Rush et al, 2006). Additionally, there is a substantial time-lag in response: 2 to 4 weeks for initial effect, and 6 to 12 weeks for maximal efficacy. Treatment-resistant depression (TRD) is associated with substantial psychosocial dysfunction, morbidity, and mortality, due in part to suicide and under-treated medical co-morbidities. Thus, there is a need for better and more rapid-acting anti-depressants to quickly alleviate the burden of depression for patients (Niciu et al, 2014; Fond et al, 2014). 

Treatment-resistant depression has no standard definition; it is commonly described, as it was in clinical trials of esketamine, as a major depressive disorder that has not responded adequately to ≥2 different antidepressant regimens of adequate dose and duration (Medical Letter, 2019). An assessment of the definition of treatment-resistant depression prepared for the Agency for Healthcare Research and Quality (Gaynes, et al., 2018) found only 17 percent of TRD intervention studies enrolled study populations that met this criterion. On March 5, 2019, the U.S. Food and Drug Administration (FDA) approved Spravato (esketamine) nasal spray, in conjtunction with an oral antidepressant, in adults who have treatment-resistant depression, defined as patients with major depressive disorder who, despite trying at least two antidepressant treatments given at adequate doses for an adequate duration in the current episode, have not responded to treatment. Esketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Esketamine is the S-enantiomer of racemic ketamine, and binds more potently to the NMDA receptor than the other stereoisomer. The mechanism of action of esketamine for depression is unknown (Medical Letter, 2019). The FDA approved ketamine (Ketalar) in 1970.

The efficacy of Spravato was evaluated in three short-term (four-week) clinical trials and one longer-term maintenance-of-effect trial. None of the available trials of intranasal esketamine were designed to control for the dramatic subjective effect (“high”) the drug produces (Medical Letter, 2019). There are no trials comparing intranasal esketamine to other agents used for augmentation of antidepressants.

In the three short-term studies, patients were randomized to receive Spravato or a placebo nasal spray. In light of the serious nature of treatment-resistant depression and the need for patients to receive some form of treatment, all patients in these studies started a new oral antidepressant at the time of randomization and the new antidepressant was continued throughout the trials. The primary efficacy measure was the change from baseline on a scale used to assess the severity of depressive symptoms. In one of the short-term studies, Spravato nasal spray demonstrated statistically significant effect compared to placebo on the severity of depression, and some effect was seen within two days. The two other short-term trials did not meet the pre-specified statistical tests for demonstrating effectiveness. In the longer-term maintenance-of-effect trial, patients in stable remission or with stable response who continued treatment with Spravato plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant.

In Study 1 (TRANSFORM-2; NCT02418585), Spravato was evaluated in a randomized, placebo-controlled, double-blind, multicenter, short-term (4-week), Phase 3 study in adult patients 18 to less than 65 years old with treatment-resistant depression (TRD). Patients in Study 1 met DSM-5 criteria for major depressive disorder (MDD) and in the current depressive episode, had not responded adequately to at least two different antidepressants of adequate dose and duration. After discontinuing prior antidepressant treatments, patients in Study 1 were randomized to receive twice weekly doses of intranasal Spravato (flexible dose; 56 mg or 84 mg) or intranasal placebo. All patients also received open-label concomitant treatment with a newly initiated daily oral antidepressant (AD) (duloxetine, escitalopram, sertraline, or extended-release venlafaxine as determined by the investigator based on patient’s prior treatment history). Spravato could be titrated up to 84 mg starting with the second dose based on investigator discretion.

The demographic and baseline disease characteristics of patients in Study 1 were similar for the Spravato and placebo nasal spray groups. Patients had a median age of 47 years (range 19 to 64 years) and were 62% female, 93% Caucasian, and 5% Black. The newly initiated oral AD was an SSRI in 32% of patients and an SNRI in 68% of patients. In Study 1, the primary efficacy measure was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at the end of the 4-week double-blind induction phase. The MADRS is a ten-item, clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts. Spravato plus a newly initiated oral AD demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus a newly initiated oral AD.

The mean baseline (standard deviation) MADRS score in the Spravato plus an oral antidepressant (n=114) group was 37.0 (5.7) compared with 37.3 (5.7) for the placebo nasal spray plus oral antidepressant treatment group (n=109). The least-squares (LS) mean change (standard error) from baseline to end of Week 4 was -19.8 (1.3) in the Spravato group compared with -15.8 (1.3) in the placebo group. This resulted in a -4.0 LS mean difference with a 95%CI (-7.3, -0.6) between the two groups. The authors concluded that for the primary efficacy endpoint, Spravato plus an oral antidepressant was statistically significantly superior to placebo nasal spray plus oral antidepressant for the change from baseline in MADRS Total score at Week 4 in patients with treatment-resistant depression. Most of Spravato’s treatment difference compared to placebo was observed at 24 hours. Between 24 hours and Day 28, both the Spravato and placebo groups continued to improve; the difference between the groups generally remained but did not appear to increase over time through Day 28. At Day 28, 67% of the patients randomized to Spravato were receiving 84 mg twice weekly. Few subjects (<10%) had reduction in Spravato dosage from 84 mg to 56 mg twice weekly.

Study 2 (SUSTAIN-1; NCT02493868) was a long-term randomized, double-blind, parallel-group, multicenter maintenance-of-effect study in adults 18 to <65 years of age who were known remitters and responders to Spravato. Patients in this study were responders in one of two short-term controlled trials (Study 1 and another 4-week study) or in an open-label direct-enrollment study in which they received flexibly-dosed Spravato (56 mg or 84 mg twice weekly) plus daily oral AD in an initial 4-week phase.

Stable remission was defined as a MADRS total score ≤ 12 for at least 3 of the last 4 weeks. Stable response was defined as a MADRS total score reduction ≥ 50% for at least 3 of the last 4 weeks and not in remission. After at least 16 initial weeks of treatment with Spravato and an oral antidepressant, stable remitters and stable responders were randomized separately to continue intranasal treatment with Spravato or switch to placebo nasal spray, in both cases with continuation of their oral antidepressant. The primary study endpoint was time to relapse in the stable remitter group. Relapse was defined as a MADRS total score ≥22 for 2 consecutive weeks or hospitalization for worsening depression or any other clinically relevant event indicative of relapse. The demographic and baseline disease characteristics of the two groups were similar. Patients had a median age of 48 years (range 19 to 64 years) and were 66% female, 90% Caucasian, and 4% Black.

Patients in stable remission who continued treatment with Spravato plus oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than did patients on placebo nasal spray plus an oral AD. The estimated hazard ratio (95% CI) of Spravato plus oral antidepressant relative to placebo nasal spray plus oral antidepressant based on weighted estimates was 0.49 (95% CI: 0.29, 0.84). However, the hazard ratio did not appear constant throughout the trial.

Time to relapse was also significantly delayed in the stable responder population. These patients experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus oral antidepressant. The estimated hazard ratio (95% CI) of Spravato plus oral antidepressant relative to placebo nasal spray plus oral antidepressant based on Cox proportional hazards model was 0.30 (95% CI: 0.16, 0.55).

In Study 2, based on depressive symptomatology, the majority of stable remitters (69%) received every-other-week dosing for the majority of time during the maintenance phase; 23% of stable remitters received weekly dosing. Among stable responders, 34% received every-other-week dosing and 55% received weekly dosing the majority of time during the maintenance phase. Of the patients randomized to Spravato, 39% received the 56 mg dose and 61% received the 84 mg dose.

Two other studies were conducted to assess the effects of Spravato on driving skills in adults with major depressive disorder (Study 3) and in healthy subjects (Study 4). On-road driving performance was assessed by the mean standard deviation of the lateral position (SDLP), a measure of driving impairment.

Study 3 was a single-blind, placebo-controlled study in 25 adult patients with major depressive disorder that evaluated the effects of a single 84-mg dose of intranasal Spravato on next day driving and the effect of repeated administration of 84 mg of intranasal Spravato on same-day driving performance. For the single dose treatment phase, an ethanol-containing beverage was used as a positive control. The SDLP after administration of single 84-mg dose of Spravato nasal spray was similar to placebo 18 hours post-dose. For the multiple dose treatment phase, the SDLP after repeated administration of 84 mg intranasal Spravato was similar to placebo 6 hours post-dose on Day 11, Day 18, and Day 25.

Study 4 was a randomized, double-blind, cross-over, placebo-controlled study in 23 healthy subjects evaluated the effects of a single 84-mg dose of esketamine nasal spray on driving. Mirtazapine (30 mg) was used as a positive control. Driving performance was assessed at 8 hours after Spravato or mirtazapine administration. The SDLP 8 hours after Spravato nasal spray administration was similar to placebo. Two subjects discontinued the driving test after receiving Spravato because of a perceived inability to drive after experiencing post-dose adverse reactions; one subject reported pressure behind the eyes and paresthesia of the hands and feet, the other reported headache with light sensitivity and anxiety.

In their proof-of-concept study, Canuso et al (2018) compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk. In a double-blind, multicenter study, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment. The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the Montgomery-Åsberg Depression Rating Scale (MADRS). Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary endpoints included these measures at 24 hours and double-blind endpoint at day 25. A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference=-5.3, SE=2.10; effect size=0.61) and at ∼24 hours (least-square mean difference=-7.2, SE=2.85; effect size=0.65), but not at day 25 (least-square mean difference=-4.5, SE=3.14; effect size=0.35). Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67), but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache. The authors concluded that these preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide

An early phase study (Phase 2; NCT01998958) by Daly et al (2018) assessed the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). The authors state approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were re-randomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] ls) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 [2.09], P = .02; 56 mg: -6.3 [2.07], P = .001; 84 mg: -9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy). The authors concluded that the antidepressant effect of intranasal esketamine for TRD was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials.

Lapidus et al (2014) tested the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. The authors state that this study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. The authors acknowledge that the relatively small sample size is a study limitation and the use of a single dose and a single drug administration does not address important questions related to optimal dosing and the longer-term safety or efficacy of this intervention. The authors conclude that while these findings are suggestive of efficacy and of a favorable tolerability profile, much more research is required before the true efficacy and safety of this intervention can be assessed. Future studies designed to optimize dosing while identifying relapse prevention strategies and biomarkers of treatment response will provide additional needed data to maximize benefit for patients and minimize side effects.

Each of these trials compared esketamine to placebo along with the addition of a new antidepressant (an SSRI or SNRI) at the clinician’s discretion (Atlas, et al., 2019). Thus, these trials compare what may be considered the additive benefit and harm of esketamine rather than directly comparing esketamine to the use of an antidepressant. Moreover, there are no studies directly comparing esketamine to other therapies used in patients with treatment-resistant depression including augmentation with medications such as antipsychotics, transcranial magnetic stimulation, electroconvulsive therapy, as well as off-label ketamine. In addition to a lack of comparative data, differences in entry criteria, patient characteristics, study design and outcome measurement in the clinical trials of esketamine and these comparators precluded even indirect comparisons (Atlas, et al., 2019).

Further investigations into intranasal esketamine are underway.

Ketamine has been abused for its hallucinogenic effects for many years. Both ketamine and esketamine are classified as schedule III controlled substances. The Spravato labeling contains a Boxed Warning that cautions that patients are at risk for sedation and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug. Because of these risks, Spravato is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS) where pharmacies must be certified in the REMS and must only dispense Spravato to healthcare settings that are certified in the program. Spravato must only be administered to patients who are enrolled in the program. Also under the terms of the REMS program, Spravato must be administered in a certified medical office where patients are under the direct observation of a healthcare provider and are monitored for at least two hours after receiving their Spravato dose due to the risk of sedation and dissociation. Thus, the patient can self-administer Spravato nasal spray under the supervision of a health care provider in a certified doctor’s office or clinic, but the spray cannot be taken home. The health care provider will instruct the patient on how to operate the nasal spray device. During and after each use of the nasal spray device, the health care provider will check the patient and determine when the patient is ready to leave. The REMS requires the prescriber and the patient to both sign a Patient Enrollment Form that clearly states that the patient understands they should make arrangements to safely leave the health care setting to get home and that the patient should not drive or use heavy machinery for the rest of the day on which they received the drug. Additionally, Spravato must be dispensed with a patient Medication Guide that outlines the drug’s uses and risks.

The most common side effects experienced by patients treated with Spravato in the clinical trials were disassociation, dizziness, nausea, sedation, vertigo, decreased feeling or sensitivity (hypoesthesia), anxiety, lethargy, increased blood pressure, vomiting and feeling drunk.

Three patients taking esketamine in clinical trials committed suicide; whether these suicides were related to esketamine use is uncertain.

Patients with unstable or poorly controlled hypertension or pre-existing aneurysmal vascular disorders may be at increased risk for adverse cardiovascular or cerebrovascular effects. Spravato may impair attention, judgment, thinking, reaction speed and motor skills. Patients should not drive or operate machinery until the next day after a restful sleep. Spravato may cause fetal harm and women of reproductive potential should consider pregnancy planning and prevention; women should not breastfeed while being treated.

A Medical Letter assessment of Spravato (2019) concluded: "Adjunctive treatment with esketamine intranasal spray (Spravato) can produce a transient antidepressant response in patients with treatment-resistant depression (TRD). Continuous use of this very expensive drug is required to maintain improvement, and its potential for dependence and abuse is concerning. Esketamine can cause serious cardiovascular and psychological adverse effects and its long-term efficacy and safety remain to be determined."

For adults with treatment-resistant depression, a report from the Institute for Clinical and Economic Review (ICER) (Atlas, et al., 2019) considered the evidence on esketamine plus background antidepressant compared to background antidepressant alone to be "promising but inconclusive," demonstrating a moderate certainty of a comparable, small, or substantial net health benefit, and a small likelihood of a negative net health benefit. The ICER report concluded that the evidence is "insufficient" to judge the net health benefit of esketamine versus ketamine, electroconvulsive therapy, transcranial magnetic stimulation, oral antidepressants, or augmentation with antipsychotics. 

See also CPB 0938 - Ketamine for the Treatment of Depression.


Spravato (esketamine must be administered under the direct supervision of a healthcare provider. A treatment session consists of nasal administration of Spravato and post-administration observation under supervision.

Spravato is for nasal use only and is available as an aqueous solution of esketamine hydrochloride in a stoppered glass vial within a nasal spray device. Each nasal spray device delivers two sprays containing a total of 28 mg of esketamine. To prevent loss of medication, do not prime the device before use. Use 2 devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a 5-minute rest between use of each device.

Assess blood pressure prior to dosing with Spravato. Do not administer if an increase in blood pressure or intracranial pressure poses a serious risk. If baseline blood pressure is elevated (e.g., >140 mmHg systolic, >90 mmHg diastolic), consider the risks of short term increases in blood pressure and benefit of Spravato treatment in patients with treatment-resistant depression.

Because some patients may experience nausea and vomiting after administration of Spravato, advise patients to avoid food for at least 2 hours before administration and to avoid drinking liquids at least 30 minutes prior to administration.

Administer Spravato in conjunction with an oral antidepressant.

The recommended dosage for esketamine (Spravato) is:

Induction Phase (Weeks 1 to 4): Administer twice per week: Day 1 starting dose 56 mg; subsequent dose 56 mg or 84 mg

Evidence of therapeutic benefit should be evaluated at the end of the induction phase to determine need for continued treatment.

Maintenance Phase (Weeks 5 to 8): Administer once weekly: 56 mg or 84 mg

Maintenance Phase (Weeks 9 and beyond): Administer every 2 weeks or once weekly (individualized to the least frequent dosing needed to maintain remission/response): 56 mg or 84 mg

After dosing with Spravato, reassess blood pressure at approximately 40 minutes and subsequently as clinically warranted. If blood pressure is decreasing and the patient appears clinically stable for at least two hours, the patient may be discharged at the end of the post-dose monitoring period; if not, continue to monitor.

Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should administer these medications at least 1 hour before Spravato.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

HCPCS codes covered if selection criteria are met:

Esketamine nasal spray (Spravato) - no specific code:

ICD-10 codes covered if selection criteria are met:

F33.0- F33.9 Major depressive disorder [treatment-resistant depression]
R45.851 Suicidal ideations

The above policy is based on the following references:

  1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-17.
  2. Niciu MJ, Luckenbaugh DA, Ionescu DF, et al. Ketamine's antidepressant efficacy is extended for at least four weeks in subjects with a family history of an alcohol use disorder. Int J Neuropsychopharmacol. 2014;18(1).
  3. Fond G, Loundou A, Rabu C, et al. Ketamine administration in depressive disorders: A systematic review and meta-analysis. Psychopharmacology (Berl). 2014;231(18):3663-3676.
  4. Gaynes BN, Asher G, Gartlehner G, et al. Definition of treatment-resistant depression in the Medicare population. Technology Assessment Program. Project ID: PSYT0816. Prepared by RTI - UNC Evidence-Based Practice Center under Contract No. HHSA290201500011I_HHSA29032006T. Rockville, MD: Agency for Healthcare Research and Quality; February 2018.
  5. U.S. Food and Drug Administration (FDA). FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. FDA News Release. Silver Spring, MD: FDA; March 5, 2019. 
  6. Janssen Pharmaceuticals, Inc. Spravato (esketamine) nasal spray. Prescribing Information. Reference ID: 4399464. Titusville, NJ: Janssen; revised May 2019.
  7. Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: Results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2018;175(7):620-630.
  8. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry. 2018;75(2):139-148.
  9. Lapidus KA, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014;76(12):970-6.
  10. [No author listed]. Esketamine nasal spray (Spravato) for treatment-resistant depression. Med Lett Drugs Ther. 2019;61(1569):54-56.
  11. Atlas S, Agboola F, Fazioli K, et al. Esketamine for the treatment of treatment-resistant depression: Effectiveness and value. Evidence Report. Prepared for the Midwest Comparative Effectiveness Public Advisory Council (CEPAC). Boston, MA: Institute for Clinical and Economic Review (ICER); May 9, 2019.