SUMMARY

• Concomitant use of SPRAVATO nasal spray with central nervous system (CNS) depressants (eg, benzodiazepines, opioids, alcohol) may increase sedation. Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants.¹
• Studies in Patients with Treatment-Resistant Depression (TRD)
  • In phase 3 clinical trials with SPRAVATO, patients who were taking benzodiazepines at dosages equal to or less than the equivalent of 6 mg/day of lorazepam during the screening/prospective observational phase could continue these medications during the double-blind induction phase. No dose increases beyond the equivalent of 6 mg/day of lorazepam or new benzodiazepine medications were permitted during the SPRAVATO induction phase, except for the use of permitted benzodiazepine rescue medication.^2,3
    • Rescue medication for agitation or anxiety: as required, midazolam (maximum dose 2.5 mg orally or intramuscularly) or short acting benzodiazepine given on the dosing day.
  • Across clinical studies, benzodiazepines and non-benzodiazepine sleeping medication (e.g., zolpidem, zaleplon, eszopiclone, and ramelteon) were prohibited within 12 hours prior to the start of each intranasal treatment session or cognition testing.^2,3
• Studies in Patients with Major Depressive Disorder (MDD) and Suicidal Ideation with Intent
  • In a post hoc analysis of two studies (ASPIRE-I and -II),^4,5 68.5% of a total of 451 patients received concomitant benzodiazepines.⁶
  • There was no significant difference in the efficacy of SPRAVATO-treated patients with or without concomitant benzodiazepines. In the SPRAVATO + Standard of Care (SOC) group, the incidence of sedation was higher in those taking benzodiazepines vs those without.⁶

Clinical Data

Studies in Patients with Treatment Resistant Depression (TRD)

The number of patients using benzodiazepines in TRD studies are listed in Table: Concomitant Benzodiazepine Use in SPRAVATO Phase 3 TRD Clinical Trials.

Studies in Patients with MDD and Suicidal Ideation with Intent

Diekamp et al (2020)⁶ conducted a post hoc, pooled analysis of two 4-week, double-blind, placebo-controlled studies (ASPIRE-I and ASPIRE-II) in adult patients (18-64 years) with MDD with active suicidal ideation with intent to examine the effect of benzodiazepines on the efficacy and safety of SPRAVATO.^4,5 Patients were randomized to either SPRAVATO 84 mg or placebo (PBO) twice-weekly for 4 weeks plus SOC, including initial inpatient hospitalization and newly initiated or optimized antidepressant therapy.

Patients were permitted to take benzodiazepines equivalent to 6 mg or less of lorazepam daily during the study; however, patients were not allowed to take the benzodiazepine 8 hours before the dose of SPRAVATO, 4 hours following the first dose of SPRAVATO, and within 8 hours of the day 2 assessments due to its sedating effects that could confound efficacy and safety assessments. Benzodiazepine users were defined as patients taking benzodiazepine medications between day -2 to day 2 (24 hours post-first dose).  

Nearly 70% (309/451) of ASPIRE study patients received concomitant benzodiazepines. Of the 227 patients who received SPRAVATO+SOC, 159 received benzodiazepines; of the 225 patients who received PBO+SOC, 150 received benzodiazepines.

Efficacy: Pooled ASPIRE-I and ASPIRE-II Studies

Change in Montgomery and Asberg Depression Rating Scale (MADRS)

A decrease in the mean MADRS score from baseline to 24 hours post-first dose (primary endpoint) favored SPRAVATO plus SOC compared to placebo plus SOC in improving depressive symptoms in the overall study group.

• Mean MADRS (standard deviation [SD]): SPRAVATO+SOC: -16.1 (11.73) vs PBO+SOC: -12.6 (10.56)
  • Least-squares mean difference (LSMD): -3.7; 95% confidence interval (CI): -5.76,   -1.59

Improvement of depressive symptoms was also observed with SPRAVATO-treated patients vs placebo-treated patients in the subgroup of patients with or without benzodiazepine use.

• Patients with benzodiazepines: LSMD (95% CI): -4.3 (-6.63, -1.89)
• Patients without benzodiazepines: LSMD (95% CI): -3.1 (-6.62, 0.45)

Among SPRAVATO-treated patients, no statistically significant difference was observed in the reduction of MADRS total score between patients taking benzodiazepines (mean [SD]:   -15.8 [11.27]) vs patients not taking benzodiazepines (-16.8 [12.82]) (LSMD [95% CI]: 1.1 [-2.24, 4.45]).

On day 2, the proportion of patients who were responders and proportion of patients in remission numerically favored the SPRAVATO+SOC group vs PBO+SOC group, regardless of benzodiazepine use. Response was defined as ≥50% reduction from baseline in MADRS. Remission was defined as MADRS ≤12.

Safety: Pooled Data from ASPIRE-I and ASPIRE-II Studies

Dissociation

Similar incidences of dissociation were reported among the subgroups treated with concomitant benzodiazepine and those not taking concomitant benzodiazepines. The mean Clinician-Administered Dissociative States Scale (CADSS) score was increased 40 minutes from predose within the SPRAVATO+SOC group compared to the PBO+SOC group, and the increase was similarly observed in both subgroups. Mean CADSS total scores returned to predose levels 1.5 hours postdose in all analysis groups. See Table: Treatment-Emergent Dissociation and Sedation by Benzodiazepines Use in ASPIRE Studies (Safety Analysis Set).

Sedation

The incidence of sedation in patients in the SPRAVATO+SOC group with concomitant benzodiazepine use was greater than those not taking benzodiazepines. The same analysis showed a significantly lower incidence of sedation in the PBO+SOC group with or without benzodiazepine use. See Table: Treatment-Emergent Dissociation and Sedation by Benzodiazepines Use in ASPIRE Studies (Safety Analysis Set).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENTDrug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 04 April 2025.