What is the risk versus benefit of esketamine nasal spray (Spravato®)? How does the cost compare to other agents in its class?

Comment by InpharmD Researcher

The efficacy of esketamine as a rapidly acting antidepressant for severely depressed patients including those with active suicidal ideation has been extensively studied (see Table 1 to 5). Intranasal esketamine’s rapid action acts as an advantage over other antidepressants, eliciting an almost immediate clinical response in hours or days compared to weeks for other similarly indicated medications. Although both serious and non-serious adverse events have been reported with short-term esketamine use, most adverse events in clinical trials have been categorized as mild to moderate and transient. A 2020 assessment of FDA Adverse Event Reporting System (FAERS) reports found serious adverse events were most often associated with patients taking esketamine doses of 84 mg compared with 56 mg, females, patients with higher body weights, patients receiving antidepressant polypharmacy, and concomitant use of mood stabilizers, antipsychotics, benzodiazepines, or somatic medications. Institute for Clinical and Economic Review (ICER) compared eskatmine and ketamine in 2019. For treatment-resistant depression, first-year and annual costs with esketamine ranged from $30,800 to $39,400 while ketamine ranged from $2,500 to $5,300 (see additional cost analyses in Tables 6 and 7).

Background

Several review articles have discussed esketamine use for treatment resistant depression along with therapeutic drug monitoring recommendations. Esketamine is shown in clinical trials to be effective for the short-term treatment of depression and reduction in suicidality rate as monotherapy and in combination with other antidepressants compared to placebo. Intranasal esketamine’s advantage over other antidepressants was identified as its ability to elicit an almost immediate clinical response in hours or days compared to weeks for other similarly indicated medications. Although both serious and non-serious adverse events have been reported with short-term esketamine use, most adverse events in clinical trials have been categorized as mild to moderate and transient. Overall, the authors suggest new generation antidepressants, including esketamine, are as effective as classical agents based on results from clinical studies. Providers are encouraged to personalize therapy and weigh the risk/benefit of antidepressant medication choices by monitoring for adverse effects and patient response to treatment. [1], [2]

In a 2021 systematic review and meta-analysis (N= 24 trials, 1877 participants), the efficacy and tolerability of racemic ketamine and esketamine were compared for unipolar and bipolar major depression. Overall, ketamine demonstrated a significant improvement in response (RR 2.0382, 95% CI 1.5748 to 2.6380) and remission rates (RR 2.0029, 95% CI 1.5005 to 2.6735) compared to control. A subgroup analysis was performed comparing ketamine and esketamine. When compared to intranasal esketamine, intravenous ketamine was again observed to demonstrate more significant overall response (RR 3.01 vs.1.38; p= 0.0023) and remission rates (RR 3.70 vs. 1.47; p= 0.0012). Additionally, drop-outs due to adverse events were significantly lower with ketamine (RR 0.76 vs. 1.37, p= 0.0331). [3]

A 2020 post-marketing analysis discussed safety concerns of esketamine based on FDA Adverse Event Reporting System (FAERS) reports. After its 2019 US approval, 962 patients had 2,274 esketamine-related adverse events, with 389 being serious, including 22 deaths. The most frequently reported adverse events were dissociation (n= 212; 9.32%; mean onset time [MOT] 20.3 days), sedation (n= 173; 7.6%; MOT 19.1 days), drug ineffectiveness (n= 119; 5.23%; MOT 12.2 days), nausea (n= 75; 3.3%; MOT 28.1 days), vomiting (n= 74; 3.25%; MOT 14.3 days), depression (n= 65; 2.86%; MOT 3.6 days), suicidal ideation (n= 64; 2.81%; MOT 8.3 days), anxiety (n= 63; 2.77%; MOT 11.5 days), increased blood pressure (n= 62; 2.73%; MOT 10.6 days), dizziness (n= 56; 2.46%; MOT 15.7 days), product dose omission (n= 45; 1.98%; MOT 32.6 days), and feeling abnormal (n= 43; 1.89%; MOT 8.4 days). Serious adverse events were significantly more likely in patients taking esketamine doses of 84 mg compared with 56 mg, females, patients with higher body weights, patients receiving antidepressant polypharmacy, and concomitant use of mood stabilizers, antipsychotics, benzodiazepines, or somatic medications. However, age and the duration of therapy did not significantly confer serious adverse event risk. Based on these findings, the authors concluded that esketamine has a clear potential to cause serious adverse events, requiring further risk-benefit assessments to provide accurate safety outcome evaluations. [4]

A report published by the Institute for Clinical and Economic Review (ICER) in 2019 stated that sufficient evidence is available demonstrating short-term clinical benefits of esketamine taken with a background antidepressant when compared to a background antidepressant alone. However, the committee expressed concerns regarding study criteria used to define treatment-resistant depression, as well as a lack of long-term safety and efficacy data. Insufficient evidence was available to distinguish between esketamine and ketamine, repetitive transcranial magnetic stimulation, electroconvulsive therapy, or concomitant olanzapine. Esketamine was stated to exceed commonly accepted thresholds for cost-effectiveness of $50,000 to $150,000 per quality-adjusted life year (QALY) gained or per life-year gained when compared to background antidepressants. The list price for esketamine was reported to be 25-50% higher than ICER’s value-based benchmark. A cost-analysis comparison to ketamine was performed for treatment-resistant depression; first year and annual costs with esketamine ranged from $30,800 to $39,400, while the same assessment with ketamine ranged from $2,500 to $5,300. Ultimately, esketamine was deemed to provide low long-term value relative to its cost. [5]

References:

[1] Swainson J, Thomas RK, Archer S, et al. Esketamine for treatment resistant depression. Expert Rev Neurother. 2019;19(10):899-911. doi:10.1080/14737175.2019.1640604
[2] Protti M, Mandrioli R, Marasca C, Cavalli A, Serretti A, Mercolini L. New-generation, non-SSRI antidepressants: Drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others. Med Res Rev. 2020;40(5):1794-1832. doi:10.1002/med.21671
[3] Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis [published correction appears in J Affect Disord. 2020 Nov 20;:]. J Affect Disord. 2021;278:542-555. doi:10.1016/j.jad.2020.09.071
[4] Gastaldon C, Raschi E, Kane JM, Barbui C, Schoretsanitis G. Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System. Psychother Psychosom. 2021;90(1):41-48. doi:10.1159/000510703
[5] ICER Issues Final Report and Policy Recommendations on Esketamine for Treatment-Resistant Depression. Institute for Clinical and Economic Review. Updated June 20, 2019. Accessed October 13, 2022. https://icer.org/news-insights/press-releases/trd_final_report/
Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

What is the risk versus benefit of esketamine nasal spray (Spravato®)? How does the cost compare to other agents in its class?

Please see Tables 1-7 for your response.

 

Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I)

Design

Phase 3, double-blind, multicenter, international study

N= 226

Objective

 To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder (MDD) symptoms, including suicidal ideation

Study Groups

Placebo (n= 112)

Esketamine (n= 112)

Inclusion Criteria

 Age 18 to 64 years, diagnosis of MDD, clinical need of acute psychiatric hospitalization due to imminent suicide risk, Montgomery-Asberg Depression Rating Scale (MADRS) score > 28 predose on day 1

Exclusion Criteria

Bipolar disorder, obsessive-compulsive disorder, antisocial personality disorder, borderline personality disorder, moderate-to-severe DSM-5 substance or alcohol use disorder 6 months prior to screening, current or prior Diagnostic and Statistical Manual of Mental
Disorders fifth edition (DSM-5) diagnosis of psychotic disorder, positive urine test result for cocaine, amphetamines, or phencyclidine

Methods

 Patients were randomized (1:1) to receive esketamine 80 mg or placebo nasal spray BID for 4 weeks, each with comprehensive standard of care that included psychiatric hospitalization and initiation of oral antidepressants as deemed appropriate.

Duration

 24 hours after the first dose

Outcome Measures

Primary: change in MADRS total score from baseline to 24-hours post-first dose

Secondary: change in Clinical Global Impression of severity of Suicidality Revised (CGI-SS-r) score from baseline to 24-hours, safety

Baseline Characteristics

  

Placebo (n= 112)

Esketamine (n= 112)

  

Age, years

 37.9 40.8  

Female

65.2% 58.0%  

Race

White

Black/African American

Asian

Other

 

66.1%

25.0%

6.3%

2.7%

 

68.8%

25.0%

3.6%

2.7%

  

MADRS total score

 41.0 41.3  

Suicide attempt in the last month

 27.7% 28.6%  

Results

Endpoint

Placebo (n= 112)

Esketamine (n= 112)

 Least-square mean difference (95% confidence interval [CI]; p-Value)

Change in MADRS total score from baseline to 24-hours post-first dose

 -12.8 -16.4 -3.8 (-6.56 to -1.09; p= 0.006)

Change in Clinical Global Impression of severity of Suicidality Revised (CGI-SS-r) score from baseline to 24-hours

--

--

0.0 (-1.00 to 0.00; p= 0.107)

Adverse Events

 Most common adverse events reported in the esketamine group were dizziness, dissociation, headache, nausea, and somnolence

Study Author Conclusions

 These findings demonstrate rapid and robust efficacy of esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorders who have active suicidal ideation with intent.

InpharmD Researcher Critique

 Patients included in the study may have been unstable and affected by other standards of care they received during treatment. Standards of care may also differ based on location of treatment in this multi-national study.



References:

Fu DJ, Ionescu DF, Li X, et al. Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I). J Clin Psychiatry. 2020;81(3):19m13191. Published 2020 May 12. doi:10.4088/JCP.19m13191

Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II)

Design

Double-blind, randomized, placebo-controlled, multicenter study

N= 227

Objective

 To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation

Study Groups

Esketamine (n= 114)

Placebo (n= 113)

Inclusion Criteria

Age 18 to 64 years, diagnosis of MDD, clinical need of acute psychiatric hospitalization due to imminent suicide risk, MADRS score > 28 predose on day 1

Exclusion Criteria

Bipolar disorder, obsessive-compulsive disorder, antisocial personality disorder, borderline personality disorder, moderate-to-severe DSM-5 substance or alcohol use disorder 6 months prior to screening, current or prior DSM-5 diagnosis of psychotic disorder, positive urine test result for cocaine, amphetamines, or phencyclidine

Methods

Patients were randomized (1:1) to receive esketamine 80 mg or placebo nasal spray BID for 4 weeks, each with comprehensive standard of care that included psychiatric hospitalization and initiation of oral antidepressants as deemed appropriate.

Duration

 24-hours after the first dose

Outcome Measures

Primary: change in MADRS total score from baseline to 24-hours post-first dose

Secondary: change in Clinical Global Impression of severity of Suicidality Revised (CGI-SS-r) score from baseline to 24-hours, safety

Baseline Characteristics

  

Esketamine (n= 114)

Placebo (n= 113)

  

Age, years

 40.2 41.4  

Female

 60.5% 59.3%  

Race

White

Black/African American

Asian

Other

 

80.7%

6.1%

0.9%

12.3%

 

77.0%

7.1%

1.8%

14.2%

  

MADRS total score

39.5

39.9

  

Suicide attempt in the last month

31.6%

21.2%

  

Results

Endpoint

Esketamine (n= 111)

Placebo (n= 112)

 Least-square mean difference (95% confidence interval [CI]; p-Value)

Change in MARDS total score from baseline to 24-hours post-first dose

-15.7

-12.4

-3.9 (-6.60 to -1.11; p= 0.006)

Change in CGI-SS-r from baseline to 24-hours

 Primarily presented as a graph. Both groups exhibited lower suicidality but was not statistically different   

Adverse Events

 The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia.

Study Author Conclusions

This study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent.

InpharmD Researcher Critique

 The trial design was identical to ASPIRE-I with similar outcomes reported along with limitations. 

 

References:

Ionescu DF, Fu DJ, Qiu X, Lane R, Lim P, Kasper S, Hough D, Drevets WC, Manji H, Canuso CM. Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II). Int J Neuropsychopharmacol. 2021 Jan 20;24(1):22-31. doi: 10.1093/ijnp/pyaa068. PMID: 32861217; PMCID: PMC7816667.

 

Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study

Design

Randomized, double-blind, active-controlled, multicenter, phase 3 study

N= 223

Objective

 To compare the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray

Study Groups

Esketamine (n= 114)

Placebo (n= 109)

Inclusion Criteria

Age 18 to 64 years, single-episode (> 2 years) or recurrent major depressive disorder without psychotic features, Mini International Neuropsychiatric Interview, score > 34 on the Inventory of Depressive Symptomatology–Clinician Rating (IDS-C), moderate to severe depression, treatment-resistant depression, medically stable, able to self-administer

Exclusion Criteria

Recent suicidal behavior or ideation, psychotic disorder, bipolar or related disorders, antisocial histrionic or narcissistic personality disorder, obsessive-compulsive disorder, intellectual disability, autism, uncontrolled hypertension, seizures, history of moderate or severe substance use disorder, positive urine test results for drug of abuse (e.g. cannabinoids, methadone, etc.)

Methods

Patients were randomized (1:1) to receive esketamine 56 or 84 mg nasal spray or placebo. Both administered twice weekly combined with newly-initiated oral antidepressants selected by investigators.

Duration

 28 days

Outcome Measures

Primary: change in Montgomery Asberg Depressing Rating Scale (MARDS) score from baseline to day 28

Secondary: > 50% decrease in MARDS score by day, early response defined as > 50% decrease n MARDS score by day 2, safety

Baseline Characteristics

  

Esketamine (n= 114)

Placebo (n= 109)

  

Age, years

 44.9 46.4  

Female

65.8% 57.8%  

Race

Asian

Black/African American

White

Multiple

 

0.9%

5.3%

93.0%

0.9%

 

0.9%

4.6%

93.6%

0.9%

  

Concomitant antidepressant

Duloxetine

Escitalopram

Sertraline

Venlafaxine extended-release

 

52.6%

18.4%

14.0%

14.9%

 

56.0%

15.6%

14.7%

13.8%

  

Results

Endpoint

Esketamine (n= 114)

Placebo (n= 109)

 Difference between groups (95% confidence interval [CI]; p-Value) or p-Value

Change in MARDS score from baseline to day 28

-21.4

-17.0

-4.0 (-7.31 to -0.64; p= 0.02)

> 50% decrease in MARDS score by day

7.9%

4.6%

0.321

Early response defined as > 50% decrease n MARDS score by day 2

18/109 (16.5%)

11/102 (10.8%)

--

Adverse Events

 Treatment-emergent adverse events (TEAEs) in the esketamine group were dizziness, dissociation, dysgeusia, verigo, and nausea (incidence ranging from 20.9% to 26.1%). Incidence was 2- to 10-times lower in the placebo arm versus the comparator.

Study Author Conclusions

 Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.

InpharmD Researcher Critique

 Patients with significant concomitant psychiatric illness were excluded. While generally observed as safe when the primary condition was treatment-resistant depression, the effectiveness and safety in these subpopulations remain uncertain as patients are likely to exhibit multiple psychosocial conditions.



References:

Popova V, Daly EJ, Trivedi M, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study [published correction appears in Am J Psychiatry. 2019 Aug 1;176(8):669]. Am J Psychiatry. 2019;176(6):428-438. doi:10.1176/appi.ajp.2019.19020172

 

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression

Design

Phase 3, multicenter, double-blind, randomized, withdrawal study

N= 297

Objective

 To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with treatment-resistant depression (TRD) in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.

Study Groups

Stable remission 

Esketamine (n= 90)

Placebo (n= 86)

Stable response:

Esketamine (n= 62)

Placebo (n= 59)

Inclusion Criteria

 Age 18 to 64, recurrent or single-episode MDD, > 34 score on Clinician-rated Inventory of Depressive Symptomatology, total MARDS score > 28, non-responders to at least 1, but no more than 5, antidepressants in current depressive episodes

Exclusion Criteria

History of psychotic disorder, suicidal behavior, current or recent homicidal or suicidal ideation or intent, diagnosis of MDD with psychotic features, moderate or severe substance or alcohol use disorder within 6 months

Methods

Patients were randomized to receive esketamine 56 or 84 mg nasal spray or placebo. After 16 weeks of treatment, the remaining patients (n=297) were randomized into the withdrawal phase to either continue esketamine nasal spray or discontinue treatment by being switched to a placebo spray along with oral antidepressants. Patients who achieved either stable remission (MADRS score ≤12 for ≥3 of the last 4 weeks, with 1 excursion [MADRS score >12] or 1 missing MADRS assessment permitted at week 13 or 14 only) or stable response (defined as ≥50% reduction in MADRS score from baseline in the last 2 weeks of the optimization phase but without achieving remission) were measured separately for analysis.

Duration

  

Outcome Measures

 Relapse in patients who received stable remission and response group, safety
    Stable remission Stable response

Baseline Characteristics

  

Esketamine (n= 90)

Placebo (n= 86)

 Esketamine (n= 62)  Placebo (n= 59)

Age, years

 45.4 46.2 47.2 46.7

Female

64.4% 68.6% 61.3% 71.2%

Race

Black

White

Other

Multiple

Not reported

 

4.4%

88.9%

2.2%

1.1%

3.3%

 

7.0%

88.4%

1.2%

0

2.3%

 

3.2%

91.9%

4.8%

0

%

 

1.7%

1.7%

93.2%

1.7%

1.7%

Suicidal ideation in the past 6 months

20.0%

16.3%

32.3%

23.7%

Results

Endpoint

Stable remission

 

Stable response

 

Esketamine (n= 90)

Placebo (n= 86)

Esketamine (n= 62)

Placebo (n= 59)

Relapse

24 (26.7%)

39 (45.3%)

 16 (25.8%)

34 (57.6%)

Hazard ratio comparing stable remission and response groups (95% confidence interval [CI])

p-Value

0.49 (0.29 to 0.84)

0.003

0.30 (0.16 to 0.55)

< 0.001

 

Adverse Events

 Common adverse events for esketamine-treated patients included transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4% to 27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo.

Study Author Conclusions

Continued treatment with esketamine nasal spray plus an antidepressant can sustain antidepressant effects among patients with treatment-resistant depression to a greater extent than an oral antidepressant alone.

InpharmD Researcher Critique

 Patients with more severe psychotic behaviors were excluded, limiting the generalizability of the study.



References:

Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2019;76(9):893-903. doi:10.1001/jamapsychiatry.2019.1189

 

Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1)

Design

Phase 3, double-blind, multicenter study

N= 346

Objective

To compare the efficacy and safety of fixed doses of esketamine nasal spray plus a newly initiated oral antidepressant to a newly initiated oral antidepressant (active comparator) plus a placebo nasal spray in adult patients with treatment-resistant depression (TRD)

Study Groups

Esketamine 56 mg (n= 117)

Esketamine 84 mg (n= 116)

Placebo (n= 113)

Inclusion Criteria

Age 18 to 64 years with recurrent major depressive disorder (MDD) or single-episode MDD without psychotic features confirmed by Mini-International Neuropsychiatric Interview, moderate-to-severe depression unresponsive to treatment confirmed at a screening phase

Exclusion Criteria

Suicidal ideation with intent to act within the prior 6 months or suicidal behavior within the prior year; diagnosis of psychotic disorder, bipolar, or related disorders; moderate or severe substance use disorder within the prior 6 months; positive test result for drugs of abuse

Methods

Patients were randomized (1:1:1) based on a computer-generated randomization schedule to double-blind nasal spray treatment with either 1 or 2 fixed doses of esketamine, 56 or 84 mg, or matching placebo administered twice-weekly intranasally for 4 weeks under direct supervision at the study site. An open-label antidepressant was added for all patients from four options: duloxetine, escitalopram, sertraline, or venlafaxine extended-release (ER) and must be one that the patient had not previously received. Oral doses were administered daily for 4 weeks and titrated as mandated by a predefined protocol. Patients could switch to another oral antidepressant.

Montgomery-Asberg Depression Rating Scale (MADRS) was measured via telephone by independent investigators blinded to the study protocol and patient clinical status. MADRS were performed two days before nasal spray dosing.

Duration

 4 weeks

Outcome Measures

Primary: change in MADRS from day 1 to day 28

Baseline Characterisitics

  

Esketamine 56 mg (n= 117)

Esketamine 84 mg (n= 116)

 Placebo (n= 113)

Age, years

 46.4 45.7 46.8

Female

70.4% 69.3% 71.7%

Race

Asian

Black/African American

White

Other

Multiple

Not reported

 

1.7%

6.1%

79.1%

7.0%

0

6.1%

 

0.9%

6.1%

74.6%

10.5%

0

7.9%

 

1.8%

4.4%

76.1%

8.8%

0.9%

8.0%

Duration of current antidepressant episode, weeks

202.8

212.7

193.1

Oral antidepressant

Duloxetine

Escitalopram

Sertraline

Venlafaxine ER

 

42.6%

22.6%

20.9%

13.9%

 

37.7%

20.2%

21.1%

21.1%

 

38.9%

21.2%

22.1%

17.7%

Results

Endpoint

Esketamine 56 mg (n= 117)

Esketamine 84 mg (n= 116)

Placebo (n= 113)

Change in MADRS from day 1 to day 28

-19.0 ± 13.86

-18.8 ± 14.12

-14.8 ± 15.07

Least-square difference vs placebo (95% confidence interval [CI])

p-Value

-4.1 (-7.67 to 0.49)

0.027

-3.2 (-6.88 to 0.45)

0.088

--

Adverse Events

The most common (>20%) adverse events reported for esketamine plus oral antidepressant were nausea, dissociation, dizziness, vertigo, and headache

Study Author Conclusions

Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified.

InpharmD Researcher Critique

 Patients with significant psychiatric conditions were excluded, limiting the generalizability of the study results. Non-significance was found for the higher esketamine 84 mg dose which questions the acceptability of the statistical significance of the lower 56 mg dose.



References:

Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, Vitagliano D, Blier P, Fava M, Liebowitz M, Ravindran A, Gaillard R, Ameele HVD, Preskorn S, Manji H, Hough D, Drevets WC, Singh JB. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019 Oct 1;22(10):616-630. doi: 10.1093/ijnp/pyz039.

 

Cost-Effectiveness of Esketamine Nasal Spray for Patients With Treatment-Resistant Depression in the United States

Design

Cost analysis 

N= N/A

Objective

To estimate the cost-effectiveness of esketamine, a novel intranasally-dosed antidepressant, for patients in the United States with treatment-resistant depression

Study Groups

Usual care

Esketamine

Inclusion Criteria

Adults with the major depressive disorder who have failed two prior antidepressants: 1) Esketamine: initial treatment with esketamine nasal spray plus oral antidepressants, followed by additional antidepressants and/or psychotherapy if depressive symptoms do not respond; 2) Usual care: initial treatment with oral antidepressants, followed by additional antidepressants and/or psychotherapy if depressive symptoms do not respond.

Exclusion Criteria

N/A

Methods

A decision-analytic model, parameterized with efficacy data from phase III randomized trials of esketamine (TRANSFORM-1, TRANSFORM-2, TRANSFORM-3, SUSTAIN-1 trial), was used to simulate the effects of treatment with esketamine versus oral antidepressants over a 5-year horizon in 2015 United States dollars (USD). The incremental cost-effectiveness ratio (ICER) of esketamine was calculated as the ratio of its incremental cost to its incremental quality-adjusted life-years (QALYs) relative to usual care. A lower ICER indicates a better health-economic value.

Based on results for distinct cost-effectiveness thresholds of $50,000/QALY, $100,000/QALY, and $150,000/QALY, the value-based price of esketamine, defined as the per-dose price at which its ICER is equal to the threshold (highest price at which esketamine would be deemed cost-effective), was calculated for each threshold. 

Key model parameters included the efficacy of esketamine versus oral antidepressants (relative risk 1.39 for remission, 1.32 for response) and the monthly cost of esketamine ($5,572 for month 1, $1,699–2,244 thereafter) based on pooled efficacy data (esketamine n= 421; placebo n= 289).

Duration

Between March 2019 and December 2019

Outcome Measures

Remission and response of depression, QALYs, costs, ICERs, and value-based prices

Baseline Characteristics

 See Methods regarding model description and model input data

Results

Endpoint

Usual care

Esketamine

Difference

Fraction of time spent in health state, %

Initiation/non-response/relapse

Response

Remission

 

72.3%

2.4%

25.3%

 

66.9%

2.0%

31.1%

 

-5.4%

-0.4%

5.7%

QALYs

3.00

 3.07 0.07

QALY costs, 2015 USD

Total cost, societal perspective

Total cost, healthcare sector perspective

Cost components

Esketamine treatment costs

Medication cost

Physician and medical assistant services

Patient time

Other healthcare costs

Lost productivity costs

 

121,073

79,786

 

 

-

-

-

79,786

41,287

 

137,690

96,781

 

 

16,352

2,062

2,074

78,367

38,836

 

16,617

16,995

 

 

16,352

2,062

2,074

−1,419

−2,451

Incremental cost-effectiveness ratios, $/QALY

Societal perspective

Healthcare sector perspective

 

-

-

 

-

-

 

237,111

242,496

In probabilistic sensitivity analysis in which the model was run using parameter values drawn at random from distributions reflecting their uncertainty, there was a > 95% likelihood that esketamine’s ICER would be above $150,000/QALY. At a cost-effectiveness threshold of $150,000/QALY, esketamine’s value-based price was approximately $140/dose (versus a current price of $240/dose).

Adverse Events

N/A

Study Author Conclusions

In this decision-analytic modeling analysis, we found that esketamine is unlikely to be cost-effective for management of treatment-resistant depression at its current price of $240 per dose. Esketamine could become cost-effective by US standards if its price were to fall to $140 or less per dose. Achieving these price reductions while ensuring continued access for the patients who stand to benefit from esketamine will require careful and concerted efforts from payers and policymakers.

InpharmD Researcher Critique

Data used to stimulate esketamine are only based on a few hundred clinical trial participants and limited long-term results. The 5-year time horizon may fail to capture relevant longer-term health-economic consequences. If data were considered inadequate pertaining to the patient, relevant data were derived from the overall population with major depressive disorder which may have underestimated the degree of occupational impairment and mortality in selected treatment-resistant individuals. Due to the absence of comparative outcomes data, the study was unable to directly assess esketamine’s cost-effectiveness versus other alternatives (e.g., electroconvulsive therapy, transcranial magnetic stimulation)



References:

Ross EL, Soeteman DI. Cost-Effectiveness of Esketamine Nasal Spray for Patients With Treatment-Resistant Depression in the United States. Psychiatr Serv. 2020;71(10):988-997. doi:10.1176/appi.ps.201900625

 

Cost-per-remitter with Esketamine Nasal Spray Versus Standard of Care for Treatment-Resistant Depression

Design

 Model-based cost-effectiveness study

Objective

To estimate the annual per-patient costs associated with achieving remission (cost-per-remitter) using esketamine nasal spray with an oral antidepressant (ESK + oral AD) versus nasal placebo with an oral AD (placebo + oral AD) among patients with treatment-resistant depression (TRD)

Study Groups

ESK + oral AD

Placebo + oral AD

Inclusion Criteria

TRD patients meeting the eligibility criteria for two key Phase III clinical trials comparing outcomes with ESK + oral AD versus placebo + oral AD in a short-term (study 1 [ref 2]) and long-term (Study 2 [ref 3])

Exclusion Criteria

N/A

Methods

Four US payer perspectives were modeled and analyzed independently in Microsoft Excel, using payor-specific cost inputs where feasible: commercial (employer-sponsored private health insurance); Medicaid; Veteran’s Affairs (VA); and full-risk Integrated Delivery Networks (IDNs; network of providers that provide both healthcare services and health insurance). Efficacy rates were assumed to be the same across all four payers. Efficacy rates from 2 randomized clinical trials [ref 2, 3] were used for the ESK + oral AD arm.

Total cost-per-remitter (direct [medication costs, inpatient and outpatient visits] and indirect costs [lost productivity associated with depression]) was assessed over a 52-week period and compared between treatment arms. Costs due to lost productivity associated with different levels of depression were derived from the literature and measured based on the amount of time missed from work within a 7-day period, where all patients were assumed to be employed, except for the Medicaid payor where 76% of patients were assumed to be employed.

To account for changes in efficacy over time, patients were classified every 4 weeks as in remission (MADRS score ≤12), responding (an improvement from baseline in MADRS score ≥50), or nonresponding. Patients who experienced relapse (MADRS total score ≥22 for two consecutive weeks or hospitalization for worsening depression) were considered nonresponders for the remaining data inputs. The treatment efficacy state labels were used to apply average costs associated with those statuses according to costs estimated from other studies.

All costs were converted from annual to weekly figures and inflated to 2019 dollars.

The 4 payor options were modeled first according to a base-case scenario (using only efficacy data from study 1 and 2 [ref 2, 3] and assuming ESK treatment continuation for 7 months beyond remission), then adjusted based on 3 different sets of assumptions:

  1. STAR*D sensitivity analysis scenario: to account for the efficacy of the oral antidepressant alone in a real-world setting of less frequent clinical follow-up, the efficacy rates for the first 4 weeks of the oral placebo + AD arm were derived from the STAR*D study [ref 4]
  2. 12-month ESK treatment beyond remission sensitivity analyses scenario: the assumed treatment continuation beyond remission was extended from 7 to 12 months
  3. Total costs including lost productivity sensitivity analyses scenario: adds the impact of indirect costs

Duration

52 weeks 

Outcome Measures

 Cost-per-remitter

 

Results

 

 

 

 

 

 

 

 

Parameter

Commercial

Medicaid

 VA IDN

ESK + Oral AD

Placebo + Oral AD

ESK + Oral AD

 Placebo + Oral AD  ESK + Oral AD Placebo + Oral AD ESK + Oral AD Placebo + Oral AD

Cumulative relapse-free remission rate

 38% 7%  38%  7%  38%  7%  38%  7% 

Treatment costs§, USD

 19,584 963 15,964 881 15,964 881 19,521 837

Healthcare costs, USD

 13,437 18,053  13,373  16,937  13,962  18,893  20,470  25,688 

Total treatment and healthcare costs, USD

 33,021 19,016  29,337  17,818  29,925  19,774  39,992  26,526 

Cost-per-remitter, USD (=[Total treatment and healthcare costs]/[Cumulative relapse-free remission rate])

 85,808  253,978  76,236  237,980  77,766  264,106  103,925  354,279 

Difference (=[Placebo + oral AD] – [ESK + oral AD])

   168,169    161,744   186,340    250,354

Data provided above is for the base-case (short- [4 week] and long-term [up to 48-week] clinical trials) STAR*D sensitivity analysis scenario adjustment.

For each scenario, the cumulative relapse-free remission rates at the end of 52 weeks were the same as above.

For the 12-month ESK treatment scenario, the remitters in ESK + oral AD treatment arm incurred higher costs for continuing ESK treatment past 7 months of remission, resulting in higher cost-per-remitter compared with the base-case scenario. Still, ESK + oral AD treatment was associated with lower cost-per-remitter than the placebo + oral AD treatment for all non-Commercial payers, with direct cost-per-remitter advantages ranging from US$8148 for Medicaid to US$24,433 for IDNs. 

For the scenario accounting for lost productivity, the cost-per-remitter advantages with ESK + oral AD treatment in this scenario were greater by up to 300%, depending on payer. 

§Includes average weekly costs for a new line of treatment after a relapse – estimated to be US$21.13 for Commercial, US$18.22 for IDN, and US$19.38 for Medicaid and VA. During the first 4 weeks, patients received ESK twice weekly. During weeks 5-52, 23.3% of remitters and 54.8% of non-remitting responders received ESK once a week; the remaining received ESK once every other week. The duration of ESK treatment was the minimum of time to relapse, nonresponse, end of 7 months (for remitters only) or end of 52 weeks. All patients in both arms received oral AD until they relapsed or completed the 52-week period, whichever occurred first.

Adverse Events

 N/A

Study Author Conclusions

The estimates from this study show that esketamine nasal spray in conjunction with an oral antidepressant is a cost-efficient alternative for patients with TRD, as higher treatment costs are more than offset by improved clinical outcomes. The cost-per-remitter advantages for esketamine are particularly pronounced when considering the costs associated with lost productivity or the potential over-estimation of oral AD efficacy due to the more frequent clinical contact during esketamine trials relative to the real-world medical practice. These results provide important information to decision-makers as they contemplate the value of esketamine nasal spray as a treatment for TRD patients.

InpharmD Researcher Critique

The outcomes included in this model are based on oral AD treatment; this limitation hinders the generalizability of this data for real-world clinical scenarios in which alternative treatments are considered, such as electroconvulsive therapy (ECT) and repeated transcranial magnetic stimulation (rTMS). Notably, this analysis is based on the patient population included in the phase III clinical trials of ESK nasal spray, which may not be representative of the overall TRD population. 



References:

[1] Desai U, Kirson NY, Guglielmo A, et al. Cost-per-remitter with esketamine nasal spray versus standard of care for treatment-resistant depression. J Comp Eff Res. 2021;10(5):393-407. doi:10.2217/cer-2020-0276
[2] Popova V, Daly EJ, Trivedi M, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study [published correction appears in Am J Psychiatry. 2019 Aug 1;176(8):669]. Am J Psychiatry. 2019;176(6):428-438. doi:10.1176/appi.ajp.2019.19020172
[3] Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2019;76(9):893-903. doi:10.1001/jamapsychiatry.2019.1189
[4] 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):1905-1917. doi:10.1176/ajp.2006.163.11.1905