SUMMARY  

• For most drugs, the selection of a product’s dosing regimen is based upon efficacy, safety, and pharmacokinetics (plasma half-life)¹. In the SPRAVATO program for treatment-resistant depression (TRD), the dosing regimen also accounted for the pharmacodynamic properties of SPRAVATO nasal spray, namely durability of the antidepressant effect. This resulted in a regimen utilizing the lowest dosing frequency that would maintain response.^2,3
• From a pharmacokinetic perspective, esketamine (ESK) nasal spray doses of 56 mg and 84 mg were selected as the doses that yielded plasma ESK levels within the same range achieved by intravenous (IV) ESK 0.2 mg/kg.^4,5
  • The IV ESK dose of 0.2 mg/kg produced a similar clinical outcome as IV ketamine 0.5 mg/kg.

CLINICAL DATA

Induction Phase  

Twice-Weekly Dosing

The initial studies conducted with IV ketamine were single dose studies. In one study by Fava et al (2020)⁶, there was a rapid loss of efficacy following a single dose of IV ketamine administration shortly after the 3-day timepoint, with almost no meaningful benefit after 5 days. This suggested that weekly dosing may not be able to sustain the initial antidepressant response. Subsequently, a repeated dose study with IV ketamine (6 doses), given 3 times weekly over 2 weeks, found that the median time to relapse among responders was 18 days.⁷

A multicenter, double-blind study in adults (ages 18–64 years) was conducted by Janssen to evaluate the efficacy of 2 or 3 times weekly administration of IV ketamine in sustaining initial antidepressant effects in patients with TRD.² Patients were randomized to receive either IV ketamine (0.5 mg/kg of body weight) or IV PBO, administered over 40 minutes, either 2 or 3 times weekly, for up to 4 weeks. The results suggested that both IV ketamine regimens were effective in maintaining antidepressant efficacy over 15 days, with no additional benefit of the 3 times weekly administration. This led to the selection of twice weekly dosing frequency for the initial induction period of short-term clinical trials with SPRAVATO.

The data from the above studies suggested that initial dosing frequency does not need to be based on the pharmacokinetic properties of SPRAVATO. Rather, dosing frequency should be based on evidence for the time needed to achieve the full sustained pharmacodynamic effects and understanding of the hypothesized mechanism of action.^8-11

Optimization/Maintenance Phases

Once-Weekly & Every Other Week Dosing

In a subsequent phase 3 study (SUSTAIN-1)³, in order to understand if the frequency of dosing could be lowered further, patients initially received SPRAVATO+AD twice a week for 4 weeks, within an induction phase, followed by a frequency reduction to weekly for 4 weeks and then weekly or every other week for up to 12 weeks within the optimization phase. After an initial 16 weeks of treatment with SPRAVATO+AD, 176 (39%) patients were in stable remission (MADRS total score ≤12 in at least 3 of the last 4 weeks of the optimization phase with up to 1 excursion or 1 missing MADRS assessment permitted at week 13 or 14 only) and 121 (27%) patients were in stable response (≥50% reduction in the MADRS total score from baseline for the last 2 weeks of the optimization phase, but not in stable remission).¹² The results suggested that after tapering the dosing frequency, the antidepressant response was maintained for an additional 8 weeks.

Duration of Treatment Phase

Based upon published data with oral AD, shorter durations of initial AD treatment are associated with an elevated risk of relapse.¹³ Therefore, the initial 16-weeks of treatment (induction + optimization phases) was chosen to reduce the likelihood of relapse within the randomized-withdrawal (maintenance) phase of the SUSTAIN-1 study.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 12 March 2024.