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Esketamine (Spravato) for Treatment Resistant Depression

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The Disease Burden

Esketamine (Spravato) by Johnson and Johnson, received local market authorization in October 2021 for use ‘with an oral antidepressant (SSRI or SNRI) in treatment-resistant depression (TRD)’, which is defined as major depressive disorder (MDD) in adults who have not responded adequately to at least 2 different antidepressants of an adequate dose and duration to treat the current depressive episode. 

MDD is estimated to affect over 300 million people globally and has significant clinical, humanistic and economic burden. Approximately one-third of patients with MDD do not respond to available antidepressants, which translates into an increased risk of subsequent relapse, hospitalisation and suicide. TRD is a serious condition with high burden, poor outcomes and few treatment options to date. There is a wide range of guideline-directed treatment approaches which include psychotherapy, electroconvulsive therapy, alternative medication (e.g. lithium, TCAs, antipsychotics) and vagus nerve stimulation. The algorithmic variety highlights the need for an individualized approach. To date, Symbyax (olanzapine-fluoxetine) is the only other FDA-approved (2009) pharmacotherapy option for TRD but is not registered with the HSA.

Esketamine Drug Profile

HSA approval of esketamine in Singapore represents a novel treatment option that provides physician and patients hope in a treatment area faced with significant unmet need, limited efficacy and low patient acceptability. Esketamine is the s-enantiomer of racemic ketamine and possesses analgesic, anesthetic and antidepressant activities. Ketamine’s role in depression treatment augmentation is not new and although the drug is not approved for use globally in this manner, it has been harnessed off-label in cases of severe depression as reported in literature and local practice.

Esketamine, the modified version of ketamine, is administered via single-use nasal spray device. The intranasal formulation allows it to bypass the oral bioavailability issues with ketamine, facilitating quicker onset. It is intended for self-administration at site of care under medical supervision due to the high relative risk of dissociation and sedation. Upon inhalation, it non-competitively binds to and blocks N-methyl D-aspartate (NMDA) receptors. This action reduces pain perception, induces sedation and produces dissociative anesthesia. For acute management of TRD, the recommended dose of esketamine is 1 spray (28mg) into each nostril (total 56mg) on day 1. This is followed by either 56mg or 84mg for 4 weeks during treatment induction, reducing to once weekly (56mg or 84mg) for another 4 weeks during ongoing maintenance therapy. 

Clinical Development Programmes

The efficacy and safety of esketamine, in conjunction with an oral antidepressant, was evaluated in 3 short-term placebo-controlled clinical trials (TRANSFORM-1, TRANSFORM-2, TRANSFORM-3), a longer-term maintenance-of-effect study (SUSTAIN-1) and a long-term open label safety study (SUSTAIN-2). Another long-term (5 year) safety continuation trial is ongoing (SUSTAIN-3). Across the Phase III trials, 33-40% of randomized patients had failed therapy using ≥ 4 antidepressant medications.

The primary endpoint investigated in TRANSFORM was improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28 and treatment response was defined as ≥ 50% reduction from baseline in total MADRS score. Although the overall findings were generally in favor of esketamine over placebo, of the 3 short-term efficacy trials, only TRANSFORM-2 was able to demonstrate the superiority of esketamine while the other 2 trials demonstrated similar mean differences in change scores without statistical significance. The main characteristics and outcomes of the TRANSFORM and SUSTAIN-1 trials are summarized in Table 1.  

Trial Design Primary Efficacy Outcome Safety
TRANSFORM 1 (NCT02417064)

Adults with TRD, age < 65y

Esketamine 56mg (n=115) vs

Esketamine 84mg (n=114) vs

Placebo (n=113)

All groups: + daily open-label oral antidepressant 

Change from baseline to week 4 at the MADRS: 

Difference of least squares (LS) mean: -3.2; 95% CI=-6.88, 0.45; p=0.88

>20% reported nausea, dissociation, dizziness, vertigo and headache
TRANSFORM 2 (NCT02418585)

Adults with TRD, age < 65y 

Esketamine flexible dose (n=114) vs

Placebo (n=114)

All groups: + daily open-label oral antidepressant 

Change from baseline to week 4 at the MADRS:

Difference of LS means=−4.0; 95% CI=−7.31, −0.64

  • Five most common AEs were dissociation, nausea, vertigo, dysgeusia and dizziness 
  • 7% of the treatment arm discontinued the study drug vs 0.9% in the placebo arm. 
  • AEs generally resolved within 1.5h of dose
TRANSFORM-3 (NCT02422186)

Elderly with TRD, age > 65

Esketamine flexible dose (n=72) vs

Placebo (n=65)

All groups: + daily open-label oral antidepressant 

Change from baseline to week 4 at the MADRS: 

Median unbiased estimate of treatment difference (95% CI): 3.6 (-7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059

  • Six most common AEs (>12%) were dizziness, nausea, increased BP, fatigue, headache and dissociation.
  • 5.6% of the treatment arm discontinued the study drug vs 3.1% in the placebo arm. 
  • Most TEAEs were mild or moderate and resolved on the nasal dosing day.
SUSTAIN-1 (NCT02493868)

Maintenance of effect study – patients who achieved stable remission or stable response with esketamine were recruited

Randomized to: 

  1. Continue esketamine (n=152) or; 
  2. Switch esketamine to placebo (n=145)

All groups: + daily open-label oral antidepressant 

Time to relapse: 

  • Patients who achieved stable remission and who were continued on esketamine had a 51% reduced risk of relapse vs the placebo switch arm (HR 0.49; 95% CI 0.29-0.84) 
  • Patients who achieved stable response and who were continued on esketamine had a 70% reduced risk of relapse vs the placebo switch arm (HR =0.30; 95% CI 0.16-0.55)
  • The most common TEAEs reported were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo.

Clinical Practice Considerations for Esketamine

The esketamine clinical trial programmes recruited individuals at high risk of imminent suicidal behavior. These patients have been traditionally excluded from clinical trials examining the efficacy of antidepressant treatments, representing a population of severely ill individuals with a desperate need for rapid amelioration of symptoms. Encouragingly, data from TRANSFORM-2 provided statistically significant evidence for flexibly dosed esketamine nasal spray in combination with an oral antidepressant in producing a clinically meaningful and rapid reduction of depressive symptoms (as measured through the MADRS score), compared to placebo nasal spray plus oral antidepressant. TRANSFORM-1 and TRANSFORM-3 however, narrowly missed statistical significance for primary efficacy but were considered to have demonstrated clinically meaningful effects. Critically, response was observed to be rapid and effective in patients deemed treatment-resistant, providing physicians a chance to change the trajectory of an acute episode. 

However, questions remain about the cost-effectiveness of therapy, monitoring requirements, accessibility, addictive potential, risk of misuse and the optimal duration or frequency. These concerns may limit its widespread adoption in clinical practice. Furthermore, comparative effectiveness to alternative TRD treatment approaches have not been systematically investigated and its appropriate place in therapy remains a matter of uncertainty. It must also be considered that the high intensity of care that was provided to patients in these trials is likely not reflective of real-world practice and stands to further limit the real-world applicability of findings.  

Notwithstanding the limitations and caveats at play, intranasal esketamine offers an innovative new option for TRD although further work is needed to better elucidate the full spectrum of its efficacy and safety implications.

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