Esketamine (Spravato)

Number: 0950

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Scope of Policy

This Clinical Policy Bulletin addresses esketamine (Spravato) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

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 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

  1. Exclusion 

    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.

  2. Prescriber Specialties

    This medication must be prescribed by or in consultation with a psychiatrist.

  3. 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:

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

      1. For treatment-resistant depression (TRD), member must meet both of the following:

        1. Member has experienced inadequate response during the current depressive episode with two antidepressants from at least two different classes (different mechanisms of action) at the maximally tolerated labeled dose, each used for at least 8 weeks. Examples of antidepressant classes include, but are not limited to:

          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)
          7. Serotonin modulators (e.g., Trintellix, vortioxetine, Viibryd, vilazodone); 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. For major depressive disorder (MDD) with acute suicidal ideation or behavior, member meets both of the following:

        1. Member has major depressive disorder with 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. 

    Aetna considers all other indications as experimental and investigational. 

  4. Continuation of Therapy

    1. Treatment-resistant depression (TRD)

      Aetna considers 6 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

Experimental and Investigational

Aetna considers the following (not an all-inclusive list) as experimental and investigational for prediction of response to esketamine because the effectiveness of these approaches has not been established:

  • Use of blood-based biomarkers;
  • Use of pharmacogenomics (including GRIN2B, GRIA1, and BDNF polymorphisms testing)


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

CPT codes not covered for indications listed in the CPB:

Blood-based biomarkers, pharmacogenomics – no specific code

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


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. 

Capuzzi and 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.

Blood-Based Biomarkers for Prediction of Response to Esketamine

Medeiros et al (2022) stated that (R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) could produce rapid and substantial anti-depressant effects.  However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit.  Many potential peripheral biomarkers have been reported, but their current use is unclear.  In a systematic review and meta-analysis, these investigators examined the association between baseline levels and longitudinal changes in blood-based biomarkers, and response to ketamine/esketamine.  Of the 5,611 citations identified, 56 studies were included (n = 2,801 participants), and 26 were compatible with meta-analytical calculations.  Random-effect models were used, and effect sizes were reported as standardized mean differences (SMD).  The assessments revealed that more than 460 individual biomarkers were examined.  Frequently studied groups included neurotrophic factors (n = 15), levels of ketamine and ketamine metabolites (n = 13), and inflammatory markers (n = 12).  There were no consistent associations between baseline levels of blood-based biomarkers, and response to ketamine.  However, in a longitudinal analysis, ketamine responders had statistically significant increases in brain-derived neurotrophic factor (BDNF) when compared to pre-treatment levels (SMD [95 % CI] = 0.26 [0.03 to 0.48], p = 0.02), whereas non-responders showed no significant changes in BDNF levels (SMD [95 % CI] = 0.05 [-0.19 to 0.28], p = 0.70).  The authors concluded that there was no consistent evidence to support any additional longitudinal biomarkers.  Findings were inconclusive for esketamine due to the small number of studies (n = 2).  These researchers stated that despite a diverse and substantial literature, there is limited evidence that blood-based biomarkers were associated with response to ketamine, and no current evidence of clinical utility.

Combined Esketamine and Propofol in Patients with Obesity Undergoing Painless Gastroscopy

Zheng et al (2023) stated that patients with obesity are more susceptible to hypoxemia.  Anesthetic management for patients with obesity undergoing painless gastroscopy presents a severe challenge for anesthesiologists.  Esketamine has been proven to be beneficial for ameliorating respiratory depression owing to its sympathomimetic effect; however, there are no relevant reports on its use in patients with obesity.  In a RCT, these researchers examined if esketamine can be the ideal adjuvant to propofol sedation in patients with obesity undergoing painless gastroscopy.  A total of 104 patients with obesity undergoing painless gastroscopy were randomly divided into group C (propofol+saline; n = 58) and group S (propofol+esketamine 0.25 mg/kg; n = 55).  Anesthesia was induced by 2 mg/kg propofol with saline or esketamine.  The consumption of propofol, hemodynamic parameters, duration of procedure, induction time, post-operative awakening time, and orientation recovery time were recorded.  Adverse events (AEs) and satisfaction scores were also recorded.  Propofol consumption was 274.4 ± 22.6 mg and 201.3 ± 16.6 mg in groups C and S, respectively.  The induction time of groups C and S were 25.4 ± 2.3 s and 17.8 ± 1.9 s, respectively.  The post-operative awakening times of groups C and S were 6.2 ± 1.1 mins and 4.8 ± 1.3 mins, respectively.  Hemodynamic parameters were more stable in group S than in group C.  The incidence of AEs such as injection pain, hypoxemia, hypotension, bradycardia, choking, and body movement were significantly lower in group S.  The satisfaction scores of the endoscopist and anesthesiologist were (4.58 ± 0.49 versus 3.71 ± 0.83) and (4.75 ± 0.44 versus 3.33 ± 0.92), respectively.  The authors concluded that combined esketamine and propofol improved the safety and reduced the incidence of AEs in patients with obesity during painless gastroscopy; therefore, this method is worthy of further clinical application. 

The authors stated that this study had several drawbacks.  First, the sample size was relatively small (n = 55 in the propofol+esketamine group), with certain limitations and the possibility of statistical deviation.  Second, even though a higher dose of esketamine may result in a more potent sedative effect and further reduce propofol consumption, the incidence of adverse effects may increase accordingly; thus, the optimum dosage of esketamine has yet to be determined.  Third, patients aged greater than 65 years were excluded from this study.  These investigators considered that the optimal sedation regimen for elderly patients should be determined according to the results of this study.  In the future, prospective RCTs with a larger sample size should be carried out to verify the findings of this trial.

Esketamine on Post-Partum Depression Risk in Patients Undergoing Cesarean Section

Liu et al (2023) noted that post-partum depression (PPD) is a prevalent public health issue.  Although ketamine has prophylactic effects on PPD in women undergoing cesarean section, the effects of esketamine on PPD remain unclear.  These researchers examined the effectiveness of peri-operative esketamine infusion on PPD risk by evaluating Edinburgh Postnatal Depression Scale (EPDS) scores and blood biomarkers.  A total of 150 participants undergoing elective cesarean section were randomly allocated to receive either esketamine or normal saline.  Since 27 participants were excluded due to consent withdrawal or loss to follow-up, 123 patients were included.  The primary outcome was the prevalence of PPD risk.  Secondary outcomes included the prevalence of post-partum anxiety (PPA) risk, levels of biomarkers, post-operative pain intensity, and cumulative sufentanil consumption.  The prevalence of PPD and PPA risk at 3 days, 42 days, 3 months, and 6 months post-partum did not differ between the 2 groups.  In addition, EPDS scores, pain intensity at rest, and during coughing on post-operative days (POD) 1 and 2 did not differ between the 2 groups.  Sufentanil consumption during 0 to 12 hours, 12 to 24 hours, 0 to 24 hours, and 0 to 48 hours post-operatively were significantly lower in the esketamine group compared to the control group.  Blood biomarkers did not differ between the 2 groups on POD 3.  The authors concluded that peri-operative administration of esketamine did not decrease the incidence of PPD risk in women following elective cesarean section; however, esketamine reduced opioid consumption.  Moreover, these researchers stated that further investigation is needed to determine the optimal time/route and dose of esketamine injection for the prevention of PPD. 

The authors noted that this trial had several drawbacks.  First, these investigators did not use the American Psychiatric Association's DSM-5, to diagnose PPD, although a threshold EPDS score of 12/13 has been validated.  Furthermore, EPDS item 10 was not considered separately to identify at-risk individuals.  Second, these researchers did not collect data on several PPD risk factors, such as race, psychiatric history, stressful life events, pregnancy complications, obesity, and low-birth-weight infants, which may affect these findings.  Third, the timing and dose of esketamine administration used in this study may not be generalizable to other peri-operative esketamine administration protocols for PPD.  Fourth, the plasma levels of C-reactive protein (CRP), interleukin (IL)-6, and BDNF were measured on post-operative day 3, but not at post-operative week 6.  These data may not reflect depression risk at 6 weeks post-partum.  Blood levels of reproductive hormones such as estradiol and progesterone may be important for PPD after cesarean section although these researchers did not measure these hormones in this study.  Further research on measurement of these hormones is needed.  Fifth, given a lower incidence of PPD risk the sample size in the current study was insufficient to power the primary outcome, and inferences should be interpreted with caution; thus, further studies with a larger sample size are needed to confirm these results.  The authors stated that the prophylactic effect of esketamine administration for PPA risk needs to be further examined.  Depression during pregnancy is a risk factor for PPD; therefore, it is important to evaluate the prophylactic effect of esketamine on PPD in high-risk population.

Yang et al (2023) stated that the optimal dosage and method of esketamine for PPD symptoms (PPDS) are unclear.  In a RCT, these investigators examined the effect of different doses of esketamine on PPDS in women undergoing cesarean section, with evidence of pre-natal depression.  The 3 groups were high- (2 mg/kg) and low-dose (1 mg/kg) esketamine via (PCIA, following an initial IV infusion of 0.25 mg/kg esketamine, compared to placebo (0.9 % saline infusion).  All groups also received the sufentanil (2.2 μg/kg).  The primary outcome was the incidence of PPDS at 7 and 42 days post-partum.  The secondary outcomes included the remission from depression and total EPDS scores at 7 days and 42 days post-partum; mean change from baseline in the EPDS score; post-operative analgesia.  0.25 mg/kg of esketamine IV infusion combined with 1 mg/kg (n = 99) or 2 mg/kg (n = 99) esketamine PCIA reduced PPDS incidence at 7 days post-partum (p < 0.05), with high-dose esketamine PCIA also reduced PPDS incidence 42 days post-partum (p < 0.05), compared to placebo (n = 97).  Low- and high-dose esketamine PCIA lowered numeric rating scale (NRS) scores at rest within 48 hours post-operatively (p < 0.01), with high-dose esketamine also reducing the NRS score during movement at 48 hours post-operatively (p = 0.018).  Neither high- nor low-dose esketamine PCIA increased post-operative adverse reactions (p > 0.05).  The authors concluded that esketamine (0.25 mg/kg) IV infusion combined with 1 mg/kg or 2 mg/kg esketamine PCIA appeared safe and with few adverse effects in the management of PPDS and pain in women undergoing cesarean section.  These researchers stated that the tolerability and safety of esketamine requires further investigation based on more specific scales; the transient side effects of esketamine could have biased the staff and patients.

Non-Intranasal Esketamine for the Treatment of Depression

Moeller et al (2022) stated that difficult-to-treat-depression (DTD) is a clinical challenge.  The interventions that are well-established for DTD are not suitable or effective for all the patients; thus, more therapeutic options are needed.  These investigators formulated an evidence-based guideline concerning 6 interventions not well-established for DTD in Denmark.  They did not find adequate evidence to recommend intravenous (IV) ketamine/esketamine, rumination-focused psychotherapy, or cognitive remediation to patients with DTD.  The authors concluded that the evidence supported 2 of the 6 reviewed interventions; however, it was generally weak, emphasizing the need for more good quality studies.   

Smith-Apeldoorn et al (2022) noted that the introduction of esketamine into the field of psychiatry comes on the heels of excitement from studies on racemic ketamine.  While the intra-nasal route has been the most studied to date, other modes of administration of esketamine may also be of interest in the management of depression.  These investigators examined the literature on non-intranasal esketamine for depression in terms of its anti-depressant effect and safety.  They searched PubMed, Embase, the Cochrane Library, and Google Scholar from inception up to February 2021.  Search terms included a combination of Medical Subject Headings and text words indicative of esketamine and depression.  These researchers selected both controlled and uncontrolled studies examining non-intranasal esketamine for the treatment of depression.  They identified 4 RCTs on IV esketamine and 15 open-label studies on IV (n = 80), subcutaneous (SC; n = 73), and oral (n = 5) esketamine.  These researchers found IV, SC, and possibly oral administration of esketamine to be effective in reducing depressive symptoms in most patients with MDD, bipolar depression, and severe TRD.  Clinical response to repeated administration of esketamine persisted over the course of treatment.  Esketamine was well-tolerated by most patients, but open-label data indicated marked psychotomimetic symptoms in exceptional cases.  The overall quality of the controlled studies was considered high, the overall quality of the uncontrolled studies low-to-moderate.  The authors concluded that IV, SC, and possibly oral esketamine may offer a safe and effective addition to the depression treatment armamentarium.  However, as most included studies lacked a control group and had small sample sizes, the quality of these findings was limited.  Different types and formulations of ketamine remain to be compared directly.

Surjan et al (2022) stated that affective disorders account for most cases of suicide.  The pharmacological arsenal to treat suicidality is limited and available agents take too long to take effect.  A large body of evidence shows optimal results of ketamine for treating depression, but the evidence concerning suicidality has not been fully described.  These investigators reported the 1st real-world study of severely depressed patients presenting with suicide ideation who were treated with repeated administration of SC esketamine.  They analyzed data from 70 acutely depressed subjects diagnosed with resistant MDD or bipolar depression.  Subjects were administered SC esketamine once-weekly for 6 weeks.  The primary effectiveness endpoint, the change from baseline to 24-hour post-administration 6 in the item 10 Montgomery-Asberg Depression Rating Scale score, was analyzed using a mixed-effects repeated-measures model.  There were significant effects for time on item 10 Montgomery-Asberg Depression Rating Scale scores (p < 0.0001) but not for a time × diagnosis interaction (p = 0.164) from baseline to the end of the study.  Effectiveness of esketamine did not differ between groups (MDD versus bipolar depression) at any time-point.  Statistical significance on suicidality scores was observed from 24 hours after the 1st administration (p < 0.001), and a further reduction was observed with repeated administrations.  Esketamine was safe and well-tolerated.  Mean heart rate (HR) remained stable during the administrations and the blood pressure (BP) increase was self-limited.  The authors concluded that repeated SC esketamine administration had significant anti-suicidality effects in both MDD and bipolar groups, with a rapid onset of action and a good tolerability profile.  Moreover, these researchers stated that large RCTs are needed to confirm these preliminary findings.

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.

Pharmacogenomics for Guidance of Esketamine Treatment Planning

Meshkat et al (2021) noted that ketamine is a dissociative anesthetic used worldwide for anesthesia, pain management, TRD and suicidality.  Predictors of anti-depressant response and adverse effects to ketamine remain poorly understood due to contradictory results.  In a systematic review, these investigators examined the available evidence evaluating pharmacogenomic predictors of ketamine clinical benefits and adverse effects.  Electronic databases were searched from inception to July 2021 to identify relevant articles.  A total of 12 articles entailing 1,219 participants with TRD, 75 who underwent elective surgeries and received ketamine as an anesthetic, 49 with pain, and 68 healthy participants met the inclusion criteria and enrolled to this review.  While identified articles reported mixed results, 3 predictors emerged: Val66Met (rs6265) brain derived neurotrophic factor (BDNF; Met allele) was associated with reduced antidepressant and anti-suicidal effects; CYP2B6*6 (e.g., CYB2B6 metabolizer) was associated with more severe dissociative effects; and NET allelic (rs28386840) variant were associated with greater cardiovascular complications (e.g., moderate-to-severe treatment emergent hypertension).  Several important limitations were identified, most notably the small sample sizes and heterogeneity of study design and results.  The authors concluded that preliminary evidence suggested the potential for pharmacogenomic testing to inform clinical practices; however, further research is needed to better determine genetic variants of greatest importance and the clinical validity of pharmacogenomics to help guide ketamine treatment planning.

Beanes et al (2022) examined the effect of genetic variants in glutamate ionotropic receptor N-methyl-d-aspartate type subunit 2B (GRIN2B), glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type subunit 1 (GRIA1), and BDNF genes on therapeutic response, remission, and total Montgomery-Asberg Depression Rating Scale scores after treatment with ketamine or esketamine in TRD patients.  Participants (n = 60) were from a double-blind, randomized, non-inferiority clinical trial comparing single-dose IV ketamine (0.5 mg/kg) to esketamine (0.25 mg/kg) for TRD.  Montgomery-Asberg Depression Rating Scale was applied at baseline, 24 hours, 72 hours, and 7 days post-infusion to evaluate depressive symptoms.  Blood samples were collected to examine single nucleotide polymorphisms (SNPs) rs1805502 (GRIN2B), rs1994862 (GRIA1), and rs6265 (BDNF).  There was no association between rs1805502, rs1994862, or rs6265 polymorphisms and anti-depressant response (p = 0.909, p = 0.776, and p = 0.482, respectively), remission (p = 0.790, p = 0.086, and p = 0.669), or Montgomery-Asberg Depression Rating Scale scores at each time-point (p = 0.907, p = 0.552, and p = 0.778).  The authors found no association between the studied SNPs (rs6265, rs1805502, and rs1994862) and ketamine's therapeutic action in TRD patients.  These researchers stated that further studies with larger samples are needed to clarify the use of these genes of interest as predictors for anti-depressant treatment.


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: Accessed October 5, 2022.
  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. Beanes G, Caliman-Fontes AT, Souza-Marques B, et al. Effects of GRIN2B, GRIA1, and BDNF polymorphisms on the therapeutic action of ketamine and esketamine in treatment-resistant depression patients: Secondary analysis from a randomized clinical trial. Clin Neuropharmacol. 2022;45(6):151-156.
  5. 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.
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