SUMMARY

• Although select phase 3 clinical trials in treatment-resistant depression and major depressive disorder (MDD) with active suicidal ideation and intent permitted the concomitant use of certain classes of augmentation therapies, no analyses have been conducted to evaluate the efficacy or safety of SPRAVATO in combination with a specific antidepressant (e.g., mirtazapine), mood stabilizer (e.g., lithium), or antipsychotic (e.g., aripiprazole).^1-5
• Two-double-blind (DB), randomized, placebo (PBO)-controlled studies, ASPIRE I,¹ and ASPIRE II,²evaluated the efficacy and safety of SPRAVATO in addition to comprehensive standard of care (SOC) for the reduction of depressive symptoms 24 hours after first SPRAVATO dose in those who have MDD and active suicidal ideation with intent.
  • SOC consisted of initial hospitalization and the initiation or optimization of AD therapy (either AD monotherapy or AD plus augmentation therapy).^1,2
  • 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.
• A post hoc pooled analysis of the ASPIRE I and ASPIRE II clinical trials found that SPRAVATO+SOC reduced depressive symptoms 24 hours after first SPRAVATO dose in adults with MDD and active suicidal ideation with intent compared with PBO+SOC, regardless of the type of oral AD SOC (monotherapy or augmentation) administered.⁶
  • The safety profile was similar in patients receiving SPRAVATO plus AD monotherapy and those receiving SPRAVATO plus AD and augmentation therapy and was consistent with the overall known safety profile of SPRAVATO.
• A post hoc analysis of pooled data from the ASPIRE I and ASPIRE II trials in patients who received AD + atypical antipsychotic (AP) augmentation as SOC indicated that SPRAVATO+SOC reduced depressive symptoms at 24 hours after first dose to a greater degree compared with PBO+SOC. No new adverse events were identified.⁷

Clinical data

Post Hoc Analyses of ASPIRE I and II in Patients Who Received AD Monotherapy SOC vs AD + Augmentation SOC

Lynum et al (2020)⁶ conducted a post hoc analysis of pooled data from two randomized, double-blind, phase 3 studies (ASPIRE I and ASPIRE II) designed to assess the efficacy and safety of AD monotherapy and AD + augmentation therapy, given as SOC AD therapies in combination with SPRAVATO in patients with MDD and active suicidal ideation with intent.⁶

Concomitant SOC AD Therapies

Augmentation medications for MDD considered to be SOC included typical and atypical antipsychotics, lithium, anticonvulsant agents, and any additional ADs used in conjunction with another AD. Benzodiazepines and nonbenzodiazepine hypnotics and anxiolytics were not considered SOC for depression.

The SOC medications most frequently prescribed during the double-blind phase are shown in Table: Ten Most Commonly Prescribed SOC Medications.

Efficacy – Pooled Phase 3 Studies (ASPIRE I & ASPIRE II)

Change in Montgomery-Åsberg Depression Rating Scale (MADRS)

The change in MADRS total score from baseline to 24 hours after first SPRAVATO dose was the primary efficacy endpoint. The difference between treatment groups in the change of MADRS total score from baseline to 24 hours after first SPRAVATO dose was statistically significant (P=0.005) for SPRAVATO+SOC vs PBO+SOC. An analysis by SOC type showed similar treatment differences in favor of SPRAVATO+SOC in patients receiving AD monotherapy SOC (-4.0 [-6.8-1.3]) and patients receiving AD + augmentation SOC (-3.9 [-6.6, -1.2]). A similar trend in favor of SPRAVATO+SOC can be seen at 4 hours postdose and over the 25-day course (see Figure: [A] Changes in MADRS Total Score From Baseline at 4 and 24 Hours After First Dose Based on ANCOVA Models and [B] Changes in MADRS Total Score Over Time Based on MMRM ANCOVA Models).

Change in Clinical Global Impression of Severity of Suicidality-Revised Scale (CGI-SS-r) Score

In predefined analyses, the between-group difference in CGI-SS-r score at 24 hours after first SPRAVATO dose among SPRAVATO+SOC and PBO+SOC treatment groups was not statistically significant. Changes from baseline in CGI-SS-r score and the proportions of patients with a CGI-SS-r response with SPRAVATO+SOC were similar in the AD monotherapy SOC and AD + augmentation SOC groups.⁶

Safety – Pooled Phase 3 Studies

Patients who received AD monotherapy SOC vs those who received AD + augmentation SOC experienced a generally similar treatment-emergent adverse event (TEAE) profile (Table: Summary of Safety and Most Common TEAEs).

Post Hoc Analyses of ASPIRE I and II in Patients Receiving AD + APs

Sliwa et al (2021)⁷ conducted a post hoc analysis of pooled data from the ASPIRE I and ASPIRE II trials to assess the efficacy and safety of SPRAVATO+SOC and PBO+SOC in patients who received ADs augmented with atypical APs as SOC (n=118).

Concomitant Atypical APs Prescribed as Augmentation Therapy

Quetiapine was prescribed in over half (54.2%) of the 118 patients. Aripiprazole (26.3%) and olanzapine (13.6%) were two other commonly employed APs. Risperidone (1.7%), sulpiride (1.7%), amisulpride (0.8%), brexpiprazole (0.8%), and lurasidone (0.8%) were less commonly used.

Efficacy – Pooled Phase 3 Studies (ASPIRE I & ASPIRE II)

Change in MADRS

Patients receiving SPRAVATO+SOC experienced an improvement in MADRS total score vs PBO+SOC at 24 hours after first dose (least squares mean [LSM] difference: -5.4 [95% CI: -9.5 to -1.2]). Similar findings were observed at 4 hours after first dose (LSM: -4.5 [95% CI: -8.3 to -0.8]) and at later time points (see Figure: [A] Changes in the MADRS Total Score From Baseline at 4 Hours and 24 Hours after First Dose for Patients Receiving AD Plus AP as SOC Based on ANCOVA Models and [B] Over Time for Patients Receiving AD Plus AP as SOC Based on MMRM ANCOVA Models).

Change in CGI-SS-r Score

In patients who received AD plus AP as SOC, a clinically meaningful improvement in the CGI-SS-r score (≥1-point change) was observed in a greater proportion of patients in the SPRAVATO+SOC group vs PBO+SOC group at both 4 (66.2% vs 36.0%; odds ratio [OR] [95% CI]: 3.9 [1.7-9.0]) and 24 hours (72.3% vs 47.1%; OR [95% CI]: 3.2 [1.4-7.4]) after first dose. Note that no significant differences were seen in this key secondary endpoint with the full analysis set in the ASPIRE I and ASPIRE II studies, likely because of the substantial impact of inpatient psychiatric hospitalization and twice-weekly study visits.^1,2

Safety – Pooled Phase 3 Studies

The safety profile of SPRAVATO in patients receiving AD+AP as SOC was consistent with the safety profile in the full analysis set of the ASPIRE I and ASPIRE II studies. The most common TEAEs (≥10%) included dizziness, dissociation, nausea, somnolence, headache, anxiety, dysgeusia, sedation, vomiting, vision blurred, paresthesia oral, and nasal discomfort.

Limitations

The post hoc analysis was not designed to prospectively evaluate subgroups who received ADs+APs as SOC and there were no adjustments for multiplicity. This analysis included a relatively small sample size, making it difficult to draw firm efficacy and safety conclusions. Lastly, the analysis did not control for baseline ADs to which the APs were added, which may have impacted results.

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 16 April 2024.