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SPRAVATO® (esketamine)
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Adverse Event of SPRAVATO - Sedation and Somnolence
Last Updated: 05/15/2025
SUMMARY
- Before SPRAVATO administration, instruct patients not to engage in potentially hazardous activities, such as driving a motor vehicle or operating machinery until the next day after a restful sleep.1
- Somnolence was 1 of the more common treatment-emergent adverse events (TEAE) observed in phase 3 studies (see Table: TEAEs of Sedation/Somnolence and/or MOAA/S).2
- 8 Sedative effects were measured by the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scale. Based on the MOAA/S, onset of sedative symptoms was generally observed at approximately 15 minutes after the first dose was administered, peaking at 30-45 minutes postdose and resolving by 1 to 1.5 hours postdose.3 , 4 ,9 ,10 - Post hoc analyses of 2 short-term and 2 long-term studies in TRD found that those who experienced somnolence or sedation during the first week of treatment with SPRAVATO+oral antidepressant (AD) were more likely to have somnolence or sedation recur during subsequent weeks.2,3,5
,6 ,11 ,12 - Real-world retrospective studies reported sedation rates between 14.6% and 31.7%.13
-17 - Postmarketing safety data:
- From the Risk Evaluation and Mitigation Strategy (REMS) program from 5 March 2019 to 5 January 2024, sedation was reported in 61.9% of patients in 34.7% of treatment sessions.18
- An analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS; from the first quarter of 2019 to the fourth quarter of 2023) identified 14,606 adverse events (AEs) reported for SPRAVATO, of which 688 cases were due to sedation.19
- From the Risk Evaluation and Mitigation Strategy (REMS) program from 5 March 2019 to 5 January 2024, sedation was reported in 61.9% of patients in 34.7% of treatment sessions.18
- A postmarketing evaluation of Janssen’s Global Medical Safety Database (from March 2019 through January 2023) identified 25 cases in which patients were reported to have concurrent respiratory depression AEs and sedation and/or dissociation.20
In the majority of cases, patients were using concomitant medications or had comorbidities, including anxiety disorder, obesity, alcohol abuse, and hypothyroidism (although respiratory depression cannot be attributed to these factors). - Concomitant use with central nervous system (CNS) depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation; therefore, closely monitoring for sedation is recommended with concomitant use of SPRAVATO with CNS depressants.21
PRODUCT LABELING
- Because of the risks of serious adverse outcomes resulting from sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program under a REMS called the SPRAVATO REMS.22
- Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored for at least 2 hours at each treatment session (including pulse oximetry), followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.22
- SPRAVATO may cause sedation or loss of consciousness. In some cases, patients may display diminished or less apparent breathing.22
- In clinical trials, 0.3% to 0.4% of SPRAVATO-treated patients experienced loss of consciousness (corresponding to a MOAA/s score of 0).22
BACKGROUND
The MOAA/S was used to measure treatment-emergent sedation. MOAA/S scores correlate with the levels of sedation defined by the American Society of Anesthesiologists (ASA) continuum. The level of sedation was scored on the MOAA/S 0-5 point scale9:
- 0=no response to painful stimulus (corresponding to ASA continuum for general anesthesia).
- 1=responds only after painful stimulus.
- 2=responds only after mild prodding or shaking.
- 3=responds only after name is called loudly and/or repeatedly.
- 4=lethargic response to name spoken in normal tone.
- 5=readily responds to name spoken in normal tone (awake; corresponding to ASA continuum for minimal sedation).
In the phase 3 program mild sedation corresponded with MOAA/S score 4, while moderate or greater sedation was defined as MOAA/S score ≤3.9
CLINICAL DATA
Sedative effects on the MOAA/S typically showed an onset at around 15 minutes after the first dose was administered, with symptoms peaking at 30 to 45 minutes postdose and generally resolving (ie, MOAA/S score of 5) by 1 to 1.5 hours postdose.2,3,9,10
Across all phase 2 and 3 TRD studies, the most frequently reported level of sedation in both adult and elderly subjects was mild sedation (corresponding to a MOAA/S score of 4).9
Of note, in cases of reported sedation, no symptoms of respiratory distress were observed, and hemodynamic parameters (including vital signs and oxygen saturation) remained within normal limits.9,10
TRD studies: In total, 4 patients out of the 1599 SPRAVATO-treated patients with MOAA/S scores had a score on the MOAA/S scale of 0, ie, deeply sedated and did not respond to trapezius muscle squeeze. These events were rare, and all resolved on the dosing day without any medical intervention. In all cases, pulse oximetry was within normal range, with no evidence of respiratory depression. Of note, 1 patient was taking zopiclone (non-benzodiazepine hypnotic) every night for sleeplessness, including the nights preceding intranasal dosing days. Following the events, it was noted that SPRAVATO was discontinued in 1 patient while 1 patient received a dose decrease to 56 mg.9 - MDSI studies: One patient had MOAA/S scores of 0 and 1 on multiple dosing days. On those dosing days, the patient’s vital signs were within normal range, and the patient did not require medical intervention.10
| PHASE 3 TRIALS IN TRD | |
|---|---|
| ACUTE TRIALS | |
| Trial Design | Sedation and/or Somnolence Ratesa,b |
| Popova et al (2019)2 conducted a 4-week, randomized, DB, active-controlled, multinational study to compare the efficacy and safety of flexibly dosed SPRAVATO nasal spray plus a newly initiated oral AD vs a newly initiated oral AD+PBO nasal spray in adult patients (18-64 years) with TRD Study Treatment Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff. A new oral OL AD (duloxetine, escitalopram, sertraline, or venlafaxine XR) was administered daily for the duration of the DB phase following a fixed titration schedule. Study Groups
| Somnolence (DB phase)
Percent of patients with MOAA/S ≤4 at any postdose time during DB phase
|
| Fedgchin et al (2019)3 conducted a 4-week, randomized, DB, active-controlled, multinational study to compare the efficacy and safety of fixed-dose SPRAVATO plus a newly initiated oral AD vs a newly initiated oral AD+PBO in adult patients (18-64 years) with TRD Study Treatment Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff. A new oral OL AD was initiated (see Popova et al above). Study Groups
| Somnolence (DB phase)
Sedation (DB phase)
Percent of patients with MOAA/S ≤3 at any postdose time during DB phase3
|
| Ochs-Ross et al (2020)4 conducted a 4-week, randomized, DB, active-controlled, multicenter study in elderly patients (≥65 years) with TRD which assessed the efficacy, safety, and tolerability of flexible doses of SPRAVATO plus a newly initiated oral AD compared with a newly initiated oral AD+PBO. Study Treatment Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff. A new oral OL AD was initiated (see Popova et al above). Study groups
| Somnolence (DB phase)
Percent of patients with MOAA/S ≤3 at any postdose time during DB phase4
|
| Chen et al (2023)24 Study Treatment Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff. A new OL oral AD was initiated (see the Popova et al [2019] study above). Study Groups
| Somnolence (DB phase)
|
| LONG-TERM TRIALS | |
| Daly et al (2019)5 conducted a long-term, DB, active-controlled, randomized-withdrawal, maintenance study to assess the efficacy of flexibly-dosed SPRAVATO plus an oral AD compared with an oral AD+PBO in delaying relapse of depressive symptoms in patients with TRD who were stable responders and remitters after an initial 16 weeks of treatment with SPRAVATO+oral AD. Study Treatment During the IND phase (initial 4 weeks), patients self-administered either SPRAVATO or PBO 2 times per week. In the OP (12 weeks) and MA (variable duration) phases, nasal spray medication was administered weekly for the first 4 weeks, then individualized to once weekly or once every other week based on severity of depression symptoms. A new oral OL AD (duloxetine, escitalopram, sertraline, or venlafaxine XR) was administered daily for the duration of the IND phase following a fixed titration schedule and remaining unchanged during the OP/M phase. Study Groups
| Somnolence (DB Maintenance phase)
Sedation (DB Maintenance phase)
|
| Wajs et al (2020)6 conducted an OL, multicenter, study to evaluate the long-term (up to 1 year of exposure) safety, tolerability and efficacy of flexibly-dosed SPRAVATO nasal spray (28, 56 or 84 mg) plus a newly initiated oral AD in patients with TRD. Study Treatment During the IND phase (initial 4 weeks), patients self-administered either SPRAVATO or PBO 2 times per week. In the OP/M phase (48 weeks), nasal spray medication was reduced to once weekly for the first 4 weeks, and then individualized to once weekly or once every other week based on severity of depression symptoms. A new oral OL AD was initiated (see Daly et al above). Study Groups
| Somnolence (all phases) SPRAVATO+oral AD: 16.7% (n=134) In a post hoc analysis, severe sedation was defined as MOAA/S score of 0 or 1.25 In another post hoc analysis that compared efficacy and safety of SPRAVATO+oral AD in younger (18 to 64 years; IND, n=624; OP/M, n=477) vs older (≥65 years; IND, n=155; OP/M, n=126) patients, somnolence was reported in 12.3% vs 11.0% of patients in the IND phase and 13.8% vs 15.1% of patients in the OP/M phase; sedation was reported in 6.7% vs 5.8% of patients in the IND phase and 5.0% vs 4.0% of patients in the OP/M phase.26 |
| Zaki et al (2023)27 Study Treatment During the induction phase (initial 4 weeks), patients self-administered a flexible dose of SPRAVATO 2 times per week. In the OP/MA phase (variable duration), patients administered SPRAVATO once weekly, every other week, or every 4 weeks based on CGI-S and tolerability. Study Groups Starting dose of 28 mg (patients aged ≥65 years), 56 mg, or 84 mg SPRAVATO (N=1148): induction phase, n=458; OP/MA phase, n=1110 (690 were directly enrolled; 420 were continued from the induction phase). | Somnolence (all phases)
|
| Reif et al (2023)28 Study Treatment In the treatment phase (initial 8 weeks) patients were randomized to receive flexible doses of SPRAVATO+oral AD or QUE-XR+oral AD; flexible dosing was continued for 24 weeks in the maintenance phase. SPRAVATO was administered 2 times per week during weeks 1-4, once weekly during weeks 5-8, and once weekly or every other week during weeks 9-32.29 Study Groups
| Somnolence (all phases)29
Sedation (all phases)29
|
| Phase 3 Trials in MDSI | |
| Fu et al (2020)7 Study Treatment Patients received either SPRAVATO+SOCc or PBO+SOC 2 times per week for 4 weeks followed by ~2 months of follow-up with SOC only. Study Groups 84 mg SPRAVATO+SOC (n=114) PBO+SOC (n=112) | Somnolence (DB phase)
Sedation (DB phase)
Percent of patients with MOAA/S ≤3 at any postdose time during DB phase
|
| Ionescu et al (2021)8 conducted a second identically designed study as above Study Groups 84 mg SPRAVATO+SOC (n=115) PBO+SOC (n=115) | Somnolence (DB phase)
Sedation (DB phase)
Percent of patients with MOAA/S ≤3 at any postdose time during DB phase
|
| Abbreviations: AD, antidepressant; AE, adverse event; DB, double-blind; IND, induction; MDSI, Major Depressive Disorder with Acute Suicidal Ideation or Behavior; MOAA/S, Modified Observer’s Assessment of Alertness/Sedation; OL, open-label; OP/M, optimization and maintenance; PBO, placebo; QUE-XR, quetiapine extended release; SNRI, serotonin-norepinephrine reuptake inhibitor; SOC, standard of care; SSRI, selective serotonin reuptake inhibitor; TEAE, treatment-emergent adverse event; TRD, treatment-resistant depression. a b cSOC consisted of newly initiated or optimized AD along with at least 5 days of initial hospitalization and enhanced by twice-weekly intensive visits during DB phase. | |
Williamson et al (2018)11 conducted a post hoc analysis of two 4-week, randomized, double-blind (DB) trials in patients with TRD.2,3 The objectives of the analysis were to measure if the incidence of specific AEs, including sedation, during the first week of treatment appeared to be associated with the incidence/frequency of the same AEs during week 2-4, and if the duration of time until patients were determined to be discharge-ready during week 1 was associated with the subsequent duration during weeks 2-4.
As illustrated in Table: Incidence of Somnolence in Week 1 and Incidence/Frequency of Somnolence in Weeks 2-4, the incidence of AEs of somnolence was 17.3% for 345 patients who received SPRAVATO+oral AD. Most patients (88.7%) did not report somnolence during the first week. Of those patients who experienced sedation once, twice, or not at all during the first week of treatment, the table below provides data on the associated proportion of patients who experienced a recurrence of sedation during the subsequent 3 weeks of treatment.
| AE | 4-Week Incidence | Week 1 Incidenceb (Number of Monitoring Periods [0-2] AE Observed) | Number of Patients With AEs in Weeks 2-4 | Number of Sessions (0-6) in Which an AE Was Experienced in Weeks 2-4 | |
|---|---|---|---|---|---|
| Somnolence | 17.3% | None - 88.7% (n=306) | → | 6.2% (n=19) | 2.53 |
| Once - 11.3% (n=39) | → | 71.8% (n=28) | 3.07 | ||
| Twice - 2.9% (n=10) | → | 100% (n=10) | 4.13 | ||
| Abbreviation: AE, adverse event. aData sample was a combination of data from the 3 intranasal SPRAVATO groups from the fixed-dose and flexible-dose studies (n=345). bThe first-week incidence groups are not mutually exclusive - the “Twice” group is a subset of the “Once” group. | |||||
Williamson et al (2022)12 conducted a post hoc analysis of pooled data from SUSTAIN-1 and SUSTAIN-2 trials to characterize the recurrence of AEs for SPRAVATO based on AEs that occurred during the early and later courses of treatment. Incidence, frequency, and severity of the most common AEs (ie, dizziness, dissociation, nausea, vertigo, increased blood pressure, and sedation) were evaluated.
Sedation was reported in 3.8% (36/949) of patients in week 1, see Table: Rates of Sedation Recurrence According to Frequency of Sedation Occurrence in Week 1. The frequency of sedation in week 4 was more associated to later recurrence than its week 1 frequency.
| Postdose Monitoring Period | No. of Patients | Overall Incidence (%) | None in Week 1, % (n/N)a | Once in Week 1, % (n/N)a,b | Twice in Week 1, % (n/N)a,c |
|---|---|---|---|---|---|
| Weeks 2-4 | 949 | 4.0 | 2.1 (19/913) | 36.8 (7/19) | 70.6 (12/17) |
| Weeks 5-8 | 918 | 2.6 | 1.2 (11/883) | 22.2 (4/18) | 52.9 (9/17) |
| Months 3-6 | 595 | 3.4 | 3.0 (17/575) | 0 (0/9) | 36.4 (4/11) |
| Months 6-12 | 595 | 2.5 | 1.7 (10/575) | 0 (0/9) | 45.5 (5/11) |
| Abbreviation: AE, adverse event.an/N represents the number of patients who experienced a recurrence of sedation/number of patients who contributed data to the time period depicted in the row. bDepict ≥10% of difference in AE recurrence rates between occurrence once per week vs none in week 1. cDepict ≥10% of difference in AE recurrence rates between occurrence twice vs once per week in week 1. | |||||
On stratifying patients based on the level of sedation observed during weeks 1 and 4, the average severity during recurrent episodes was reflective of mild sedation (MOAA/S score, 3.5-4.0); 1 patient had a mean MOAA/S score of 3.25, indicating moderate sedation.
Post Hoc Analysis of MDSI Studies
Fua et al (2020)30
| Study Design | Results |
|---|---|
| Gutiérrez-Rojas et al (2025)13 conducted a study in 71 patients (mean age, 54.6 years; female, 70.4%) with TRD who received SPRAVATO for up to 6 months via an early access program in Spain. | Sedation was reported in 31.0% (n=22) of patients. |
| Samalin et al (2024)14 | Somnolence was reported in 15.9% of patients, and 5 patients discontinued treatment due to somnolence. |
| Martinotti et al (2022)15 Rosso et al (2025)16 | Sedation was reported in 28.4% of patients during the REAL-ESK study.15 In the 6-month follow-up, sedation was reported in 31.7% of patients.16 |
| Brendle et al (2022)17 conducted a study in 171 patients (mean age, 36 years; female, 60.0%) with TRD who received SPRAVATO in an outpatient clinic from July 2019 to June 2021. | Sedation was reported in 22.0% (n=38) of patients. Of these patients, 74.0% experienced sedation onset within the first 30 minutes or 1 hour after SPRAVATO treatment; 97.0% (n=37/38) of patients with symptoms resolved within 2 hours. |
| Abbreviation: TRD, treatment-resistant depression. | |
REMS patient monitoring forms completed by certified United States healthcare settings and pharmacies from 5 March 2019 to 5 January 2024, identified 58,483 patients who received ≥1 SPRAVATO treatment for a total of 1,486,213 treatment sessions. Sedation was reported in 61.9% of patients in 34.7% of treatment sessions. Sedation rate decreased during the induction phase (sessions 1-8) and remained relatively consistent in the early (sessions 9-12) and late (sessions ≥13) maintenance phases, and it was consistent across sexes and age groups (<25 years, 25-55 years, and >55 years). There was a total of 2096 serious AEs, of which 1.2% (n=26) were sedation.18
An analysis of the FAERS database (from the first quarter of 2019 to the fourth quarter of 2023) evaluating 14,606 SPRAVATO-related AEs reported sedation (n=688 cases; reporting odds ratio, 172.68 [95% confidence interval (CI), 159.08-187.46]; proportional reporting ratio, 155.53 [95% CI, 144.36-167.57]; empirical Bayesian geometric mean [EBGM], 142.05 [lower limit of 90% CI for EBGM, 130.85]) as among the 5 most frequently reported AEs.19
An evaluation of the Janssen Global Medical Safety Database (from March 2019 through January 2023) identified 50 cases that involved patients who had clinical symptoms of respiratory depression on the day of administration, and either had respiratory rates and/or oxygen saturation levels below thresholds (≤10 breaths per minute and/or oxygen saturation ≤93%) or cases that failed to report either or both values.20 Of those cases, 25 were reported with concurrent respiratory depression AEs and sedation and/or dissociation (20/25 were serious AEs). AEs included dyspnea (13), oxygen saturation decreased (3), respiratory distress (2), respiratory rate decreased (2), apnea (1), cardio-respiratory arrest (1), hypopnea (1), respiratory abnormal (1), respiratory arrest (1), and respiratory disorder (1). Eighteen of these cases reported the patient as recovered (17) or recovering (1); 1 case not recovered; and 6 cases had 7 AEs with unknown outcomes (1 case involved more than 1 AE/outcome). Ten cases reported both sedation and dissociation, 9 cases reported sedation, and 6 cases reported dissociation.
Interventions were reported in 17 cases, which included hospital/emergency room services (6), medication (3), oxygen (3), stimulation (2), cardiopulmonary resuscitation (1), rescue breathing (1) and an unspecified intervention (1). Eight cases did not document an intervention. In 9 cases, patients were ready for discharge within the 2-hour observation period. In the remaining cases, patients were assessed as not ready for discharge within the 2-hour monitoring period (13), or discharge readiness was not reported (3).20
In the majority of cases, patients were using concomitant medications or had comorbidities, including anxiety disorder, obesity, alcohol abuse, and hypothyroidism (although respiratory depression cannot be attributed to these factors).20
Literature Search
A literature search of MEDLINE®
Case reports and case series (except the ones reporting management of sedation and somnolence) and real-world studies with <50 patients treated with SPRAVATO were excluded.
References
| 1 | European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP). SPRAVATO assessment report. Procedure No. EMEA/H/C/004535/0000. 2019- [cited 2025 May 5]. Available from: https://www.ema.europa.eu/en/documents/assessment-report/spravato-epar-public-assessment-report_en.pdf |
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