Esketamine (Spravato)

Number: 0950

Policy

Note: Requires Precertification.

Precertification of esketamine nasal spray (Spravato) is required of all Aetna participating providers and members in applicable plan designs. For precertification of esketamine call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (888) 267-3277.

  1. Criteria for Initial Approval

    Aetna considers esketamine (Spravato) nasal spray medically necessary for treatment-resistant depression (TRD) or major depressive disorder (MDD) with acute suicidal ideation or behavior when all of the following criteria are met (see below: Exclusion Criteria for Esketamine Nasal Spray):

    1. 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]); and
    2. The requested medication will be prescribed by or in consultation with a psychiatrist; and
    3. Member is 18 years of age or older; and
    4. Requested drug will be administered under the direct supervision of a healthcare provider; and
    5. Member will be monitored by a health care provider for at least 2 hours after administration; and
    6. Requested drug  will be used in combination with an oral antidepressant (e.g., duloxetine, escitalopram, sertraline, venlafaxine); and
    7. Member meets either of the following criteria:

      1. Member must meet both of the following:

        1. Member has experienced inadequate response during the current depressive episode with two antidepressants (e.g., selective serotonin reuptake inhibitor [SSRI], serotonin-norepinephrine reuptake inhibitor [SNRI], tricyclic antidepressant [TCA], bupropion, mirtazapine) from at least two different classes (different mechanisms of action) at the maximally tolerated labeled dose, each used for at least 8 weeks;

          1. Aminoketone (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)
          6. Tricyclic antidepressants (TCAs) (e.g., amitriptyline, desipramine, doxepin, Elavil, imipramine, Norpramin, nortriptyline, Pamelor, Surmontil, Tofranil, trimipramine); and
        2. Member has experienced an inadequate response with an adequate trial of augmentation therapyFootnote1* or evidenced based psychotherapy (e.g., cognitive behavioral therapy) during the current depressive episode; or

      2. Member has major depressive disorder with both of the following:

        1. Member has current suicidal ideation with intent defined as both of the following:

          1. Member has thoughts, even momentarily, of self-harm with at last some intent or awareness that they may die as a result, or member thinks about suicide; and
          2. Member intends to act on thoughts of killing themselves; and
        2. 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. 

    Exclusion Criteria for Esketamine Nasal Spray:

    Esketamine (Spravato) nasal spray is considered an exclusion for members with moderate or severe substance or alcohol use disorder that is not currently being treated or medically managed.

    Aetna considers all other indications as experimental and investigational. 

  2. Continuation of Therapy

    1. Treatment-resistant depression (TRD)

      Aetna considers 3 months of esketamine therapy medically necessary for the continuation of treatment of TRD when there is 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]).

    2. Major depressive disorder (MDD) with acute suicidal ideation or behavior

      Aetna considers continued treatment with esketamine (for up to 4 weeks total) medically necessary for the treatment of depressive symptoms in patients with MDD with acute suicidal ideation or behavior when member meets all initial criteria for approval. The use of Spravato beyond 4 weeks has not been systematically evaluated in the treatment of depressive symptoms in members with MDD with acute suicidal ideation or behavior.

Footnote1* 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.

Dosage and Administration

Esketamine nasal spray (Spravto) 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. 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.

Spravato is administered in conjunction with an oral antidepressant.

Treatment-Resistant Depression

Induction Phase (Weeks 1 to 4) for Adults

  • 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) for Adults

  • Administer once weekly: 56 mg or 84 mg

Maintenance Phase (Weeks 9 and beyond) for Adults

  • Administer every 2 weeks or once weekly (individualized to the least frequent dosing needed to maintain remission/response): 56 mg or 84 mg

Major Depressive Disorder (MDD) with Acute Suicidal Ideation or Behavior

The recommended dosage of Spravato for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior is 84 mg twice per week for 4 weeks. Dosage may be reduced to 56 mg twice per week based on tolerability. After 4 weeks of treatment with Spravato, evidence of therapeutic benefit should be evaluated to determine need for continued treatment. The use of Spravato, in conjunction with an oral antidepressant, beyond 4 weeks has not been systematically evaluated in the treatment of depressive symptoms in persons with MDD with acute suicidal ideation or behavior.

Source: Janssen, 2020

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

Spravato is indicated, in conjunction with an oral antidepressant, for the treatment of:

  • Treatment-resistant depression (TRD) in adults
  • Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.

    Limitations of Use

    The effectiveness of Spravato in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated.  Use of Spravato does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of Spravato. Spravato is not approved as an anesthetic agent. The safety and effectiveness of Spravato as an anesthetic agent have not been established.

Esketamine nasal spray is available as Spravato (Janssen Pharmaceuticals, Inc.). Esketamine, a schedule III controlled substance drug, is a non-selective, non-competitive N-methyl D-aspartate (NMDA) receptor antagonist. The mechanism by which esketamine exerts its antidepressant effect is unknown. The major circulating metabolite of esketamine (noresketamine) demonstrated activity at the same receptor with less affinity.

Spravato carries a black box warning for sedation, dissociation, abuse and misuse, and suicidal thoughts and behavior. Other labeled warnings and precautions include inceases in blood pressure, cognitive impairment, impaired ability to drive and operate machinery, and embryo-fetal toxicity. Spravato is contraindicated in aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation, intracerebral hemorrhage, and hypersensitivity to esketamine, ketamine, or any of the excipients. The most commonly observed adverse reactions (incidence 5% or more and at least twice that of placebo plus oral antidepressant) for treatment-resistant depression (TRD) include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk. The most commonly observed adverse reactions (incidence 5% or more and at least twice that of placebo plus antidepressant) for treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior include dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo (Janssen, 2020).

Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD)

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 greaterthan or equal 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 3 short-term (4-week) clinical trials and 1 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 3 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 1 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 2 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, multi-center, short-term (4-week), phase-III 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 2 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 2nd 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 to -0.6) between the 2 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 (less than 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  less than 65 years of age who were known remitters and responders to Spravato. Patients in this study were responders in 1 of 2 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 of less than or equal to 12 for at least 3 of the last 4 weeks. Stable response was defined as a MADRS total score reduction greater than or equal to 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 greater than or equal to 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 to 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 to 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). A total of 126 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 = 0.02; 56 mg: -6.3 [2.07], p = 0.001; 84 mg: -9.0 [2.13], p < 0.001), 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 < 0.001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95 % CI: 3.9 to 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. 

Capuzziand colleagues (2021) stated that esketamine (ESK) has been approved as a rapid-acting intranasal treatment for TRD.  Although existing studies have examined the effectiveness of ESK in the 4-week induction phase, knowledge regarding long-term effectiveness of ESK remains poor.  In a systematic review, these investigators examined the available evidence on the long-term effectiveness of ESK for the treatment of patients with TRD.  They carried out a systematic search including articles in English, up to March 31, 2021.  The search found 7 relevant studies, entailing 1,024 adult TRD patients.  Continuing treatment with ESK following the 4-week induction phase may be associated with stable effectiveness in relapse prevention among TRD patients.  Conversely, the long-term anti-depressant effectiveness upon discontinuation of ESK might be limited, although data from 3 studies had a moderate-to-high risk of bias.  Overall, the findings on the long-term effectiveness of ESK are mixed.  According to these findings, ESK treatment should be continued following the induction phase to reach a stable effectiveness in relapse prevention, while the long-term anti-depressant and anti-suicidal effects of ESK following discontinuation are inconsistent.  The authors concluded that the current level of proof of the long-term effectiveness of ESK I the treatment of patients with TRD remains low and more RCTs with larger sample sizes and active comparators are needed.  Moreover, these investigators stated that further research is needed to examine the potential risk of abuse and when and how ESK should be discontinued.  Individualization of ESK nasal spray treatment frequency may be a valuable option for optimizing the use of the compound in real world clinical practice.  Nevertheless, other molecules with more potent and longer-lasting anti-depressant effects than ESK and fewer psychomimetic side effects might be used in clinical practice in place of ESK.

Sapkota and associates (2021) noted that intra-nasal form of ESK was approved by the FDA in 2019 for TRD in adults.  Since intra-nasal ESK is a newly approved drug with a novel mechanism of action, much still remains unknown in regard to its use in TRD.  In a systematic review, these investigators examined the latest existing evidence on intra-nasal ESK; and provided a better insight into its safety and effectiveness in TRD in adults.  PubMed, Medline (via PubMed), and Google Scholar were systematically searched from 2016 to 2021, using automation tools.  After removal of duplicates and screening on the basis of title/abstract, eligibility criteria were used; and quality appraisal was carried out independently by 2 reviewers.  A total of 10 studies were selected for the final review that included 5 clinical trials (3 short-term trials, 1 withdrawal design relapse prevention study, and 1 long-term study), 3 post-hoc studies, 1 case/non-case study, and 1 review article.  Out of 3 short-term clinical trials, only 1 demonstrated a statistically significant difference between treatment with ESK plus oral anti-depressant (OAD) versus placebo plus OAD.  The result of the relapse prevention study showed significantly delayed relapse of depressive symptoms in ESK plus OAD arm when compared to placebo plus OAD arm.  Similarly, the result of the long-term clinical trial showed that the improvement in depressive symptoms was found to be sustained in those using ESK.  The most common adverse effects of ESK included nausea, dizziness, dissociation, headache, vertigo, somnolence, and dysgeusia; most were mild-moderate in severity.  One case/non-case study reported rare adverse effects including panic attacks, mania, ataxia, akathisia, self-harm ideation, increased loquacit, and autoscopy.  The authors concluded that intra-nasal ESK has shown efficacy in reducing depressive symptoms in clinical trials; however, the clinical meaningfulness of the treatment effect in the real-world population still needs to be examined.  These researchers stated that although the safety profile of ESK appeared to be favorable in most clinical trials, some serious side effects are being reported to the FDA Adverse Event Reporting System; thus, requiring further investigation.  These investigators stated that more robust clinical trials, especially long-term randomized controlled trials (RCTs) are needed to aid in providing a better evaluation regarding the safety and effectiveness of intra-nasal ESK in the treatment of TRD.

The authors stated that this systematic review had several drawbacks.  First, most of the clinical trials discussed in this review excluded patients with several significant medical/psychiatric co-morbidities, those with a history of substance use disorder, and MDD patients who were at imminent risk of suicide.  There was also a limited number of non-White patient inclusion.  This has led to limitation in the generalizability of the results.  Second, adverse effects of ESK such as dissociation and sedation could lead to potential unblinding in many of the clinical trials, which was important to be noted.  Third, 3 of the studies included in this review were post-hoc studies that could have inherent bias.  Fourth, since this review excluded gray literature, ongoing clinical trials on ESK were not included, which could have been potentially useful in reaching out additional conclusions.

Ng and colleagues (2021) noted that in recent years, ketamine and ESK treatment have demonstrated rapid anti-depressant effects in adults with TRD; however, relatively few studies have reported the effect of ketamine/ESK treatment on functional outcomes (e.g., psychosocial functioning, workplace functioning).  In a systematic review, these investigators examined the available evidence on functional outcomes with ketamine/ESK treatment in adults with TRD.  They carried out a systematic review of clinical studies reporting subjective or objective ratings of general functioning as primary or secondary outcomes.  A total of 4 RCTs, 1 open-label clinical study and 1 case series reported on the effectiveness of ketamine/ESK on subjective measures of general functioning.  Overall, mixed results were reported with respect to the effect across disparate functional measures (e.g., Sheehan Disability Scale [SDS]) using ketamine/ESK.  A single study demonstrated a significant decrease (i.e., improvement) in SDS total scores in TRD with ESK treatment; most studies, however, did not report on functional outcomes and have functional outcomes as a (co)-primary outcome measure.

The authors concluded that functional outcomes in adults with TRD receiving ketamine/ESK was insufficiently characterized.  Available evidence indicated that improvements in general psychosocial functioning was apparent.  The association, if any, between symptomatic improvement and functional improvement in TRD, as well as the temporality to improve functioning, are future research vistas.  These researchers stated that drawbacks of this review were that clinical studies that were included examined work- or social-related disability as a secondary outcome using subjective rating scales.

Major Depressive Disorder (MDD) with Acute Suicidal Ideation or Behavior

On August 3, 2020, the U.S. FDA approved the supplemental new drug application (sNDA) for Spravato (esketamine) nasal spray, taken with an oral antidepressant, to treat depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. 

The SNDA approval was based on 2 identical phase-III short-term (4-week) randomized, double-blind, multicenter, placebo-controlled studies, Study 3 (NCT03039192) and Study 4 (NCT03097133), in adults with moderate-to-severe MDD (MADRS total score greater than 28) who had active suicidal ideation and intent. In these studies, patients received treatment with esketamine nasal spray 84 mg or placebo nasal spray twice-weekly for 4 weeks. After the 1st dose, a one-time dose reduction to esketamine 56 mg was allowed for patients unable to tolerate the 84 mg dose. All patients received comprehensive standard of care treatment, including an initial inpatient psychiatric hospitalization and a newly initiated or optimized oral antidepressant (AD) (AD monotherapy or AD plus augmentation therapy) as determined by the investigator. After completion of the 4-week treatment period with esketamine /placebo, study follow-up continued through Day 90. The baseline demographic and disease characteristics of patients in Study 3 and Study 4 were similar between the esketamine plus standard of care or placebo nasal spray plus standard of care treatment groups. The median patient age was 40 years (range of 18 to 64 years), 61 % were female; 73 % Caucasian and 6 % Black; and 63 % of patients had at least 1 prior suicide attempt. Prior to entering the study, 92 % of the patients were receiving antidepressant therapy. During the study, as part of standard of care treatment, 40 % of patients received AD monotherapy, 54 % of patients received AD plus augmentation therapy, and 6 % received both AD monotherapy/AD plus augmentation therapy. The primary efficacy measure was the change from baseline in the MADRS total score at 24 hours after 1st dose (Day 2). In Study 3 and Study 4, esketamine plus standard of care demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus standard of care, with some patients starting to respond as early as 4 hours. Esketamine plus comprehensive standard of care led to a 15.9 and 16.0 point decrease on the Montgomery-Åsberg Depression Rating Scale (MADRS), a tool used to assess severity of depressive symptoms, in the 2 trials at 24 hours after the 1st dose of study medication. This compared to a reduction of 12.0 and 12.2 points in the placebo plus comprehensive standard of care group. The comprehensive standard of care included initial hospitalization, a newly initiated or optimized oral antidepressant and twice-weekly treatment visits for 4 weeks, during which patients received esketamine 84 mg or placebo nasal spray. Both the esketamine and placebo groups continued to improve between 4 hours and 25 days, with 41 % and 43 % of the esketamine plus comprehensive standard of care group achieving clinical remission of depression (minimal or no symptoms) compared with 34 % and 27 % n the placebo groups, by the end of the double-blind period, in the 2 trials, respectively.

See also CPB 0938 - Ketamine for the Treatment of Depression and Other Psychiatric Disorders.

Acute and Chronic Pain After Thoracic Surgery

Lei and colleagues (2021) noted that post-operative pain management for patients undergoing thoracoscopy surgery is challenging for clinicians; it increases both health and economic burden.  Esketamine possesses an analgesic effect twice that of ketamine.  The use of esketamine might be beneficial in alleviating acute and chronic pain following thoracic surgery.  The se researchers described the protocol aiming to examine the analgesic effect of esketamine following pulmonary surgery via visual analog scale (VAS) score for acute and chronic pain.  A prospective, randomized-controlled, double-blind, multi-center study is designed to examine the analgesic effect of esketamine in randomized patients undergoing video-assisted thoracoscopic surgery (VATS) with general anesthesia.  Patients will be randomly assigned to the esketamine Group (Group K) and control Group (Group C) in a ratio of 1:1; subjects in Group K will receive esketamine with a bolus of 0.1 mg/kg after anesthesia induction, 0.1 mg/kg/hour throughout the operation and 0.015 mg/kg/hour in patient controlled intravenous analgesia (PCIA) after surgery while subjects in Group C will receive the same volume of normal saline.  The primary outcome is to measure the pain intensity via the VAS score at 3 months after the operation.  The secondary outcome includes VAS score at 1, 4, 8, 24, and 48 hours and on the 7th day and 1 month after the operation, complications, ketamine-related neurological side effects, recovery time of bowel function, and total amount of supplemental analgesics.  These researchers stated that of the current study might illustrate the analgesic effect of esketamine for patients undergoing thoracoscopy pulmonary surgery and provide evidence and insight for peri-operative pain management.

Obsessive-Compulsive Disorder, Substance Use Disorders and Eating Disorders

Martinotti and colleagues (2021) stated that obsessive-compulsive spectrum refers to disorders drawn from several diagnostic categories that share core features related to obsessive-compulsive disorder (OCD), such as obsessive thoughts, compulsive behaviors and anxiety.  Disorders that include these features can be grouped according to the focus of the symptoms, e.g., bodily pre-occupation (i.e., eating disorders, ED) or impulse control (i.e., substance use disorders, SUD), and they exhibit intriguing similarities in phenomenology, etiology, pathophysiology, patient characteristics and clinical outcomes.  Ketamine has been indicated to produce remarkable results in patients with treatment-resistant depression, post-traumatic stress disorder (PTSD) and OCD in dozens of small studies accrued over the past 10 years, and it appears to be promising in the treatment of SUD and ED.  However, despite many small studies, solid evidence for the benefits of its use in the treatment of OCD spectrum and addiction is still lacking.  In a systematic review, these researchers examined the potential for ketamine and esketamine in treating OCD, ED and SUD, which all involve recurring and intrusive thoughts and generate associated compulsive behavior.  They carried out a comprehensive and updated overview of the literature regarding the pharmacological mechanisms of action of both ketamine and esketamine, as well as their therapeutic advantages over current treatments.  An electronic search was conducted, including all papers published up to April 2021, using the following keywords ("ketamine" or "esketamine") AND ("obsessive" OR "compulsive" OR "OCD" OR "SUD" OR "substance use disorder" OR "addiction" OR "craving" OR "eating" OR "anorexia") NOT review NOT animal NOT "in vitro", on the PubMed, Cochrane Library and Web of Science online databases.  The review was performed in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.  The use and efficacy of ketamine in SUD, ED and OCD is supported by glutamatergic neurotransmission dysregulation, which plays an important role in these conditions.  Ketamine's use is increasing, and preliminary data are optimistic.  The authors concluded that further studies are needed in order to better clarify the many unknowns related to the use of both ketamine and esketamine in SUD, ED and OCD, and to understand their long-term effectiveness.

The authors stated that his review had several drawbacks.  First, the predominance of heterogeneous studies, small samples and cross-over designs of the studies included in this review; and comparative studies with conventional therapeutic strategies were not reported in the current literature.  Second, the use of a saline placebo and not of a real control for ketamine’s psychotomimetic effects.  Third, studies had limited duration of follow-up; thus, it was not possible to estimate the long-term benefit and potential long-term consequences of ketamine/esketamine use.  This point will require additional attention from researchers.  Fourth, this review only included studies published in English.

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:

G2082 Office or other outpatient visit for the evaluation and management of an established patient that requires the supervision of a physician or other qualified health care professional and provision of up to 56 mg of esketamine nasal self-administration, includes 2 hours post-administration observation
G2083 Office or other outpatient visit for the evaluation and management of an established patient that requires the supervision of a physician or other qualified health care professional and provision of greater than 56 mg esketamine nasal self-administration, includes 2 hours post-administration observation
S0013 Esketamine, nasal spray, 1 mg
T1503 Administration of medication, other than oral and/or injectable, by a health care agency/professional, per visit

ICD-10 codes covered if selection criteria are met:

F32.0 - F32.A Major depressive disorder, single episode [treatment-resistant depression]
F33.0- F33.9 Major depressive disorder [treatment-resistant depression]
R45.851 Suicidal ideations

The above policy is based on the following references:

  1. [No author listed]. Esketamine nasal spray (Spravato) for treatment-resistant depression. Med Lett Drugs Ther. 2019;61(1569):54-56.
  2. American Psychological Association (APA). Depression Assessment Instruments. Washington, DC: APA; 2021. Available at: https://www.apa.org/depression-guideline/assessment. Accessed October 13, 2021.
  3. 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. 
  4. 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.
  5. Capuzzi E, Caldiroli A, Capellazzi M, et al. Long-term efficacy of intranasal esketamine in treatment-resistant major depression: A systematic review. Int J Mol Sci. 2021;22(17):9338.
  6. 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.
  7. DRUGDEX System [Internet database]. Armonk, NY: IBM Watson Health; Updated periodically.
  8. 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.
  9. 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.
  10. Janssen Pharmaceuticals, Inc. Spravato (esketamine) nasal spray. Prescribing Information. Reference ID: 4649523. Titusville, NJ: Janssen; revised July 2020.
  11. 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.
  12. Lei Y, Liu H, Xia F, et al. Effects of esketamine on acute and chronic pain after thoracoscopy pulmonary surgery under general anesthesia: A multicenter-prospective, randomized, double-blind, and controlled trial. Front Med (Lausanne). 2021;8:693594.
  13. Martinotti G, Chiappini S, Pettorruso M, et al. Therapeutic potentials of ketamine and esketamine in obsessive-compulsive disorder (OCD), substance use disorders (SUD) and eating disorders (ED): A review of the current literature. Brain Sci. 2021;11(7):856.
  14. Ng J, Rosenblat JD, Lui LMW, et al. Efficacy of ketamine and esketamine on functional outcomes in treatment-resistant depression: A systematic review. J Affect Disord. 2021;293:285-294.
  15. 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).
  16. 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.
  17. Sapkota A, Khurshid H, Qureshi IA, et al. Efficacy and safety of intranasal esketamine in treatment-resistant depression in adults: A systematic review. Cureus. 2021;13(8):e17352.
  18. Thase M, Connolly KR. Unipolar depression in adults: Choosing treatment for resistant depression. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed August 2021.
  19. 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.