Summary

• Major depressive disorder (MDD) is a common, debilitating, and recurrent mental health disorder. Approximately 10% to 30% of patients with MDD will not reach complete clinical remission despite multiple antidepressant pharmacologic approaches — this subpopulation is described as having treatment-resistant depression (TRD). TRD is a more challenging depressive disorder to treat and available therapies are often limited by significant psychological and physiological side effects.
• Esketamine is the S-enantiomer of racemic ketamine and is being developed as a nasal spray device for potential therapeutic use in patients with TRD. It was recently approved for marketing in the US and is under priority review at Health Canada.
• In one phase III trial, esketamine plus a newly initiated antidepressant demonstrated a statistically significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) scores relative to placebo plus a newly initiated antidepressant. Esketamine plus a newly initiated oral antidepressant also statistically significantly reduced relapse events and delayed the occurrence of a relapse event.
• Similar to ketamine, dissociative effects, sedation, and elevations in blood pressure were reported. The majority of these side effects were mild or moderate in severity and resolved within a few hours of administration.
• Esketamine’s psychoactive properties give it the potential for addiction and abuse; policies to limit off-label use and guide esketamine distribution would be important to prevent diversion. Furthermore, there remains a lack of evidence comparing intranasal esketamine to current adjunctive strategies for TRD.

Background

Major depressive disorder (MDD) is a common, debilitating, and recurrent mental health disorder. MDD is characterized by symptoms of persistent low mood, changes in appetite and sleep, fatigue, loss of motivation, interest or pleasure, or feelings of worthlessness.¹ It can also be associated with a substantial loss in productivity, quality of life, and increased mortality from suicide. MDD has a significant global burden, with an estimated 300 million people affected and reported as the leading cause of disability of all of the mental illnesses worldwide.^2–4 Within Canada, approximately 11% (4.1 million) of the population have reported a major depressive episode in their lifetime.^1,5 Even with available therapies, a significant proportion of patients will not reach complete clinical remission, with approximately 10% to 30% not responding to multiple antidepressants. ^6,7

Treatment-resistant depression (TRD) is the clinical term used to define this subpopulation of MDD patients that have not achieved optimal response to conventional therapy. TRD presents an even greater burden, with an increased risk for subsequent relapses and suicide.^8,9 Patients with TRD are also twice as likely to be hospitalized, incurring additional medical costs.^8,10 Risk factors for TRD may include old age, high stress levels, concomitant psychiatric disorders, and a history of medication nonadherence.⁶

The most common definition of TRD is the inadequate response to two or more antidepressants.^7,10,11 However, there is no clear consensus surrounding this definition, with only 17% of treatment studies closely matching this definition.¹⁰ Variations in this definition can be attributed to inconsistencies in the use of adjunctive therapies, variable dose and duration of an adequate treatment trial, and whether treatment failure occurred in the current depressive episode. As studies of emerging treatments utilize diverse definitions of TRD, it can be difficult to translate research findings into practical guidelines.

TRD is a more challenging depressive disorder to treat, with few strong recommendations in clinical practice guidelines. None of the available options have demonstrated superiority in improving clinical outcomes for patients with TRD.⁷ Available therapies are also often limited by significant side effects, such as weight gain and sedation. There remains an unmet need for a safe and effective treatment of TRD for which esketamine offers the potential to address.

The Technology

Janssen Research & Development is currently investigating esketamine for its potential therapeutic use in patients with MDD who are refractory to classical antidepressants.⁷ Esketamine is the S-enantiomer of racemic ketamine — a drug that has been used traditionally as a general anesthetic. In studies, sub-anesthetic intravenous doses of ketamine have demonstrated rapid antidepressant effects, as well as lessened fatigue and suicidality in patients with TRD and with minimal negative impacts on cognitive functioning.^12,13 Due in part to these promising results and despite concerns around limited data on long-term safety and duration of effect, ketamine’s use for depression has expanded from research settings to specialized clinics in the US and Canada servicing this patient population.^14,15

Esketamine is approximately three to four times more potent than R-ketamine, potentially translating into lower doses with fewer side effects compared with previously studied ketamine infusions.^7,16,17 Esketamine’s antidepressant effects are not mediated by known mood-modulating pathways such as the monoamine, gamma-aminobutyric acid (GABA), or opioid axes. Although the specific mechanism of action has not been fully elucidated, it is postulated that esketamine acts primarily to block the N-methyl-D-aspartate (NMDA) receptor and activate the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.

Image: Courtesy of Janssen

For TRD (defined by the manufacturer as MDD that has not responded adequately to at least two different antidepressants of adequate dose and duration in the current depressive episode), esketamine is formulated as a single-use nasal spray device.¹⁸ In contrast to intravenous ketamine, which is limited to outpatient clinics, intranasal administration is easier and could allow for increased access to therapy.¹⁹ Each device contains 28 mg of drug, delivered as one spray in each nostril.¹⁸ The maximum dose studied in clinical trials was 84 mg; therefore, multiple devices may be required. Priming of the device is not required but a five-minute rest period in-between each device is advised. For acute treatment, esketamine nasal spray requires administration twice weekly for four weeks during treatment induction, then weekly for another four weeks, followed by weekly or every other week during ongoing maintenance.¹⁸ According to the manufacturer, it is intended to be used under the direct supervision of a health care professional.

Regulatory Status

As of the publication of this report, esketamine is approved in the US for TRD; it is not approved for use in other countries or for any other indication. The manufacturer has filed for regulatory approval in Canada and the European Union for adults with TRD (defined as MDD patients who have not responded adequately to at least two different antidepressants of adequate dose and duration in the current depressive episode) based on five, phase III clinical trials (Janssen Inc., Toronto, ON: personal communication, 2019 Feb 1).^20–25 Health Canada is currently reviewing esketamine as a priority submission.²⁶

In the US, the FDA has recently approved the marketing of esketamine nasal spray, under the trade name Spravato, in conjunction with an oral antidepressant, “for the treatment of depression in adults who have tried other antidepressant medicines but have not benefited from them (treatment-resistant depression)”.²⁷ It also received Breakthrough Therapy designation in 2016 from the FDA for MDD with imminent risk for suicide; this indication is not currently approved. Of note, the FDA grants a Breakthrough Therapy designation for drugs intended to treat a serious or life-threatening disease and where initial clinical data suggests that the drug may demonstrate substantial improvement over current therapies.²⁸

Cost and Administration

The Canadian cost of esketamine is unavailable, as this product is not marketed in the country. For the US market, the manufacturer has announced that Spravato will be priced at $590 for a 56 mg dose and $885 for 84 mg.²⁹

Esketamine is developed to be administered as a nasal spray. The dosage regimen used in the completed and ongoing phase III trials is esketamine 28 mg, 56 mg, or 84 mg intranasally twice weekly for four weeks, followed by once weekly for four weeks, then once weekly or once every other week for ongoing maintenance therapy.^{18,20–24,30,31} As a result, the cost of therapy will vary based on the dose used per session and the number of treatment sessions administered, both of which can differ from patient to patient.

The budget impact is unknown, as the Canadian acquisition cost is not yet available. The budget impact will largely depend on its sequential place in therapy within the context of other treatment options currently on the market for MDD.

Target Population

For the majority of patients with MDD, available medications, psychotherapy, and alternative therapies (e.g., electroconvulsive therapy, transmagnetic stimulation) are effective at relieving symptoms and achieving disease remission. However, MDD is a complex, heterogeneous disorder, and 10% to 30% of MDD patients do not respond to a sequence of multiple traditional antidepressant therapies.^6,7

This subpopulation of patients with TRD could benefit from esketamine. However, the exact clinical need within this patient population is challenging to discern because of inconsistencies in the definitions of TRD, the variety of therapies currently available for TRD, the access to and reimbursement of non-pharmacological options, and the concurrent development of novel therapy options.

Current Practice

Because of limited evidence comparing available therapies, there is no standard treatment approach for TRD; therefore therapy should be individualized for each patient.^6,7 The Canadian Network for Mood and Anxiety Treatments (CANMAT) guideline recommends making adjustments to therapy if there is no improvement within two to four weeks of initiating the antidepressant.¹¹ The following options are recommended for managing an inadequate response:

• optimize the initial treatment
• switch the antidepressant class of drug
• add an adjunctive medication
• consider non-drug therapies.

Optimizing treatment involves increasing the dose of the current antidepressant, as tolerated, and continuing treatment for an additional six to eight weeks.¹¹ Switching to an antidepressant of a different class is an alternative for patients who had no response to therapy, or who were not tolerating the initial antidepressant. CANMAT advises this strategy may be best employed for patients in their first antidepressant trial and therefore may not be the optimal strategy for TRD (i.e., failed two or more antidepressants).

An adjunctive strategy involves adding a second medication to the initial antidepressant. This strategy includes both augmentation (i.e., adding a non-antidepressant medication) and combination (i.e., adding an antidepressant from a different class).¹¹ There is low-quality evidence to suggest that adjunctive therapy is more effective than switching therapy in patients who had a partial response to the initial antidepressant and have residual symptoms.^7,11,32 Adjunctive medications that are recommended to try first are the following atypical antipsychotic drugs: aripiprazole, quetiapine, and risperidone (off-label).^11,33 If a patient fails to respond despite these first-line options, they can trial the following adjunctive treatments: bupropion, mirtazapine, brexpiprazole, olanzapine, lithium, and thyroid hormone.¹¹ Lastly, non-drug approaches to be considered for patients with TRD include psychotherapy and neurostimulation (e.g., transcranial magnetic stimulation, electroconvulsive therapy).

Summary of Evidence

A total of five phase III trials evaluated the efficacy and safety of esketamine nasal spray in combination with a newly initiated oral antidepressant for patients with TRD; four were randomized, double-blind, active-controlled trials^21–24 and one was an open-label safety study.²⁰ There are an additional two phase III trials currently ongoing to further assess the efficacy and long-term safety of esketamine in this patient population.^30,31 Details of these trials are summarized in Table 1.

Table 1

Summary of Esketamine Phase III Trials — Patient and Trial Characteristics

In the active-controlled studies, patients were randomized to receive either esketamine nasal spray plus a newly initiated oral antidepressant or placebo nasal spray plus a newly initiated oral antidepressant. All previous oral antidepressants to which patients did not respond were discontinued.

In all of the phase III trials, TRD was defined as nonresponse (i.e., 25% or less improvement) to two or more oral antidepressants in the current episode of depression, at a therapeutic dose for at least six weeks in duration. Across the trials, approximately 33% to 40% of randomized patients had previously failed four or more antidepressants.¹⁸ Patients from all phase III trials had severe depression (MADRS greater than 34) at baseline (Janssen Inc.: personal communication, 2019 Feb 1).¹⁸

All the completed phase III trials, with the exception of SUSTAIN 1, included a four-week screening period prior to randomization. This screening period allowed for the inclusion of patients who had previously failed one antidepressant to be randomized in the trial if they also demonstrated nonresponse to a second antidepressant treatment during the screening phase.

Patients were specifically excluded from any of the five studies if they had MDD with psychotic features, had previously demonstrated nonresponse to ketamine in the current depressive episode, had a history of suicidal ideations in the past six months, or had a history of a substance or alcohol use disorder. In trials with elderly patients (i.e., TRANSFORM-3, SUSTAIN 2), additional exclusion criteria included a Mini-Mental State Examination score of less than 25, neurodegenerative disorders, or clinically significant cardiovascular disorders.

Efficacy

The results of the phase III trials are summarized here and depicted in Tables 2 and 3. These results have not yet been fully published; the data were obtained from conference poster presentations and an FDA briefing report (Janssen Inc.: personal communication, 2019 Feb 1).¹⁸

Table 2

Summary of Key Efficacy Outcomes From Four of the Phase III Trials

Table 3

Efficacy Outcomes From the Maintenance Phase of SUSTAIN 1

MADRS

This metric describes depression severity. MADRS is a clinician-rated scale consisting of 10 domains (i.e., apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), for a total possible score of 60. Higher scores indicate more severe depression and thus a decrease in scores indicate improvement. In the TRANSFORM-2 study, esketamine plus a newly initiated oral antidepressant demonstrated a statistically significant superior change in the MADRS score at day 28 (mean difference −4.0, 95% CI: −7.31 to −0.64; P = 0.010) relative to placebo plus a newly initiated oral antidepressant. Furthermore, the mean difference between treatment groups was statistically significant for almost all the time points throughout the 28 days of treatment. In the TRANSFORM-1 and TRANSFORM-3 trials, there was no statistically significant difference between esketamine and placebo.

Response Rates

In the TRANSFORM-1 and TRANSFORM-2 trials with participants between 18 to 64 years of age, 53.1% to 69.3% of patients who received esketamine in combination with a new oral antidepressant were stable responders (i.e., defined as 50% or higher reductions in MADRS depression severity scores) by day 28. In comparison, 38.9% to 52% of patients who received placebo with a newly initiated antidepressant were stable responders. In the TRANSFORM-3 trial with elderly participants (65 years-old or more), the response rate was 27.0% in the esketamine plus antidepressant group compared with 13.3% in the group receiving placebo plus a new antidepressant.

Remission Rates

In the TRANSFORM-1 and TRANSFORM-2 trials, remission rates (i.e., defined as a MADRS score of 12 or less) ranged from 36.0% to 52.5% in the esketamine plus antidepressant group compared with 31% of patients in the placebo plus antidepressant group. As with the response rates, remission rates were lower in the elderly patients studied in the TRANSFORM-3 trial: 17.5% for the esketamine plus antidepressant group versus 6.7% for the placebo plus antidepressant group. No statistical tests were reported.

Results From SUSTAIN 1 (ESKETINTRD3003):A Relapse Prevention Study

A relapse event was defined as at least two MADRS scores of 22 or greater within five to 15 days, or hospitalization for worsening depression, suicide attempt, suicide prevention, or completed suicide. According to the FDA, esketamine plus a newly initiated oral antidepressant statistically significantly delayed a relapse event, compared with placebo plus antidepressant, for both stable remitters (i.e., defined as 50% or higher reductions in MADRS score) and stable responders (i.e., defined as a MADRS score of 12 or less).¹⁸ The largest differences in relapse time between treatment groups occurred within the first two to four weeks. Esketamine also statistically significantly reduced the hazard for relapse for stable remitters (HR 0.49; 95% CI: 0.29 to 0.84, P = 0.003) and for stable responders (HR 0.30; 95% CI: 0.16 to 0.55, P < 0.001). Other efficacy outcomes data are summarized in Table 3.

Concurrent Developments

Implementation Issues

Cited concerns surrounding intravenous ketamine for depression may inform potential uptake issues for esketamine. One key concern with ketamine is its safety profile, specifically dissociative and cognitive side effects, sedation, elevations in blood pressure, and toxicity to the urinary system.⁵⁷ With the exception of cognitive dysfunction, these side effects were also reported with intranasal esketamine use (Janssen Inc.: personal communication, 2019 Feb 1). However, the majority of the urinary adverse events were mild and resolved without intervention. Dissociative symptoms, blood pressure elevations, and sedation were reported to resolve within a few hours but may require patient monitoring shortly after drug administration. Ketamine’s potential for addiction and diversion was another important concern.⁵⁷ However, post-marketing data suggests that ketamine abuse is in fact relatively uncommon.¹⁸ Much like ketamine, esketamine has psychotogenic properties that also make it susceptible to abuse; risk management could still be an important consideration.^7,16,58

Cautions currently exist surrounding driving after receiving ketamine, given the potential for dissociative and sedative side effects.^18,57 A small, double-blind, randomized phase I study assessed esketamine’s impact on driving performance.⁵⁹ Healthy patients received single doses of esketamine 84 mg intranasally, oral placebo, and mirtazapine 30 mg orally in a crossover design. There were no statistically significant differences between esketamine and placebo groups in their driving performance (i.e., measured by the weaving of a car) eight hours after drug administration, whereas mirtazapine had a significant detrimental impact on driving relative to placebo. However, the generalizability of these results to chronic esketamine use is limited. Given the prevalence of dissociation and sedation in the larger phase III trials, the risk for potential accidents and the impact on driving may still be of concern.

Although esketamine is formulated in a more convenient nasal spray device, it must be administered under direct medical supervision. This could present a challenge for patients, as it would require repeat visits to the physician’s office on a bi-weekly basis. Because of the potential driving impairment shortly after esketamine administration, travelling to the physician’s clinic and back may be problematic for patients, especially in areas with limited public transportation. The need for medical supervision also poses the question of organizing the distribution of this drug in Canada: if patients are required to obtain the medication at their retail pharmacy, policies may be required to ensure that the patient does not self-administer the medication.

There is also the potential for off-label use, as esketamine is being investigated for not only unipolar TRD but also for depression with imminent risk of suicide and treatment-resistant bipolar depression. There is also the risk of off-label use for patients with non–treatment-resistant MDD.

While there are ongoing long-term safety studies, further research is required to inform the appropriate duration of esketamine treatment and whether it can eventually be tapered or discontinued. Furthermore, there is a lack of evidence comparing intranasal esketamine to current adjunctive strategies for TRD.

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