SUMMARY

• In the clinical trials for SPRAVATO nasal spray, dissociative symptoms and transient perceptual effects, measured by the Clinician Administered Dissociative Symptoms Scale (CADSS), began shortly after the start of SPRAVATO dosing, peaked at 40 minutes, generally resolved by 1.5 hours, and attenuated with repeated dosing.^1-6
• The most common psychological effects of SPRAVATO were perceptual changes (including distortion of time, space and illusions) and dissociative symptoms (including derealization and depersonalization).^2,4,7-9
  • 61%-84% of SPRAVATO-treated patients developed dissociative or perceptual changes compared to 5%-16% of placebo (PBO)-treated patients based on the CADSS total score >4 and change >0.¹
  • Although patients with psychosis were excluded in the phase 3 treatment-resistant depression (TRD) program,^2-6 given its potential to induce dissociative effects, carefully assess patients with psychosis before administering SPRAVATO; treatment should be initiated only if the benefit outweighs the risk.¹
• In an analysis of adverse reactions from adjunctive phase 2 and phase 3 studies for TRD, of 1709 patients who were treated with SPRAVATO+newly initiated oral antidepressant, the incidence of dissociation was 40.4% (690/1709). Within the double-blind (DB) populations, dissociation was reported in 37.6% (221/587) of patients treated with SPRAVATO+oral AD and 6.2% (30/486) of patients treated with PBO+oral AD.¹⁰ See: Incidence of Dissociation.
  • A post hoc analysis of 2 long-term studies in TRD found that those who experienced an adverse event (AE) of dissociation during the first week of treatment with SPRAVATO+AD were more likely to have dissociation recur during subsequent weeks.¹¹
• A phase 4 monotherapy study found that dissociation occurred in 24.3% (55/226) of patients in the combined SPRAVATO group and 2.8% (7/250) in the placebo group during the 4week doubleblind phase, with dissociation observed in 15.6% (69/441) of SPRAVATOtreated patients during the subsequent 12week openlabel phase.¹²
• Dissociative effects are not required for the antidepressant action of SPRAVATO based on post hoc correlational analyses in TRD.¹³
• Two post hoc analyses of a long-term phase 3 study (SUSTAIN-2) did not find a correlation between clinician-reported AE of dissociation and a specific cut-off on the total CADSS score.^6,14,15
  • There was no universal profile of dissociative symptoms associated with SPRAVATO. However, symptom clusters, including changes in bodily sensations, general perceptual changes, and a general sense of being disconnected from one’s own experience (depersonalization) increased in frequency as the severity of clinicianreported AEs of dissociation increased.¹⁵
• A post hoc analysis of SUSTAIN-2 comparing the efficacy and safety of SPRAVATO nasal spray in younger (18-64 years) vs older (≥65 years) patients with TRD found that the incidences of dissociation occurred in 19.3% vs 16.7% of patients during optimization/maintenance (OP/MA) phase. The incidence of dissociation (CADSS score >4) was similar between both age groups.¹⁶
• Real-world retrospective studies reported dissociation rates between 33% and 73%.^17-22
• Postmarketing safety data:
  • From the SPRAVATO Risk Evaluation and Mitigation Strategies (REMS) program from 5 March 2019 to 5 January 2024, dissociation was reported in 65.7% of patients and 41.0% of treatment sessions. Based on the Janssen US Global Medical Safety (US-GMS) database (which captures AEs from REMS and other sources) during the same period, dissociation was reported in 2.2% of the 3985 serious adverse events (SAEs) identified.²³
  • A FAERS database analysis (Q3 2014 – Q4 2024) identified 7790 SPRAVATOrelated AEs, of which 1217 (15.6%) were dissociation.²⁴ 
  • An analysis of the EudraVigilance database (2019-2024) identified 751 SPRAVATO-related AEs; of these, 265 were considered serious AE reports and 15.8% were dissociation/dissociative disorder events.²⁵ 
• Clinical judgment should be used for managing severe dissociation that does not resolve by itself during the postadministration monitoring period. See: Management of Dissociative Symptoms.

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.²⁶
  • Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored by a healthcare provider for at least 2 hours (including pulse oximetry) at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.
  • For additional information or questions about the REMS, call 1-855-382-6022 or visit www.SPRAVATOrems.com.
• In studies in patients with major depressive disorder (MDD) and active suicidal ideation with intent, a higher proportion of patients treated with SPRAVATO+AD (84%) reported CADSS total score >4 and change >0 compared with patients treated with PBO+AD (16%).²⁶

BACKGROUND

CADSS

The CADSS is a 23-item scale with excellent inter-rater reliability and internal consistency administered to assess treatment-emergent dissociative symptoms and perceptual changes. It consists of 23 subjective items, divided into 3 components: depersonalization (items 3-7, 20, and 23), derealization (items 1, 2, 8-13, 16-19, and 21) and amnesia (items 14, 15, and 22). Participant’s responses are coded on a 5-point scale (0=not at all, 1=slightly, 2=moderately, 3=considerably, 4=extremely). The total CADSS score ranges from 0 to 92, with a higher score representing a more severe condition and scores between 0 and 4 are considered to be in the normal range.^27,28

CLINICAL DATA

Incidence of Dissociation

In an analysis of adverse reactions from phase 2 and phase 3 studies for TRD, of 1709 patients who were treated with SPRAVATO+AD, the incidence of dissociation was 40.4% (690/1709). Within the DB populations, dissociation was reported in 37.6% (221/587) of patients treated with SPRAVATO+AD and 6.2% (30/486) of patients treated with PBO+AD.¹⁰

• Dissociation included delusional perception, depersonalization/derealization disorder, derealization, diplopia, dissociation, dysesthesia, feeling cold, feeling hot, feeling of body temperature change, hallucination, hallucination - auditory, hallucination - visual, hyperacusis, illusion, ocular discomfort, oral dysesthesia, paresthesia, paresthesia oral, pharyngeal paresthesia, photophobia, time perception altered, tinnitus, vision blurred, and visual impairment.¹
• Across all phase 3 studies in TRD,^2-6 discontinuation of SPRAVATO due to dissociation occurred in 0.4% of patients.²⁹

In clinical trials in patients with MDD and active suicidal ideation with intent, dissociation was reported as follows:

• ASPIRE-I: 29.2% (33/113) and 3.6% (4/112) of patients treated with SPRAVATO 84 mg plus standard of care (SOC) and with SOC+PBO, respectively.⁷
  • In ASPIRE-I, discontinuation of SPRAVATO+SOC occurred in 4.4% of patients.⁷
• ASPIRE-II: 38.6% (44/114) and 8% (9/113) of patients treated with 84 mg SPRAVATO+SOC and with SOC+PBO, respectively.⁸
  • In ASPIRE-II discontinuation of SPRAVATO+SOC occurred in 2 patients due to dissociation.³⁰

CADSS

TRANSFORM-1 (3001)², TRANSFORM-2 (3002)³, and TRANSFORM-3 (3005)⁴ were 4week, randomized, DB, multinational studies comparing the efficacy and safety of fixed (3001) or flexibly (3002/3005) dosed SPRAVATO+AD vs AD+PBO in adult patients (1864 years; 3001/3002) and ≥65 years (3005) with TRD. Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff.

Dose-related increases in the incidence of dissociative symptoms were observed in TRANSFORM-1 and TRANSFORM-3.^2,4 See Table: Incidence of Dissociation (CADSS Total Score >4 and a Change >0) in Two Double-Blind, Randomized Studies.

Over the course of each study, the peak mean CADSS total score at the 40-minute timepoint in patients treated with SPRAVATO decreased with consecutive doses. See Figure: Mean Total CADSS Score Over Time in TRANSFORM-2.

In the ASPIRE-II study, in patients with MDD and active suicidal ideation with intent, dissociative symptoms measured by the CADSS total score began shortly after SPRAVATO dosing, peaked at the 40-minute postdose assessment, and mostly resolved by 1.5 hours. The highest mean (SD) CADSS total score after the first dose was 15.9 (12.8) in the SPRAVATO +SOC and 1.9 (4.4) in the PBO+SOC group.⁸

SUSTAIN-1 (3003)⁵ was a long-term, DB, multicenter, randomized-withdrawal, relapse prevention study to assess the efficacy of flexibly-dosed SPRAVATO+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+AD. During the induction (IND) phase (initial 4 weeks), patients selfadministered either SPRAVATO or PBO nasal spray 2 times per week. In the OP phase (12 weeks), nasal spray medication was administered weekly for the first 4 weeks; thereafter, in the OP and following MA phase (variable duration), dosing was individualized to once weekly or once every other week based on severity of depression symptoms. 

Mean changes in CADSS total score 40-minute postdose for SPRAVATO+AD patients are as follows:²⁸

• IND phase - Decreased from 6.7 (day 1) to 2.9 (day 25)
• OP phase - Decreased from 2.9 (week 1) to 2.4 (week 11)
• MA phase - Decreased from 2.7 (week 1) to 2.5 (week 32)

See Figure: Mean Total CADSS Score Over Time in SUSTAIN-1.

SUSTAIN-2 (3004)⁶ was an open-label (OL), multicenter, study to evaluate the long-term (up to 1 year of exposure) safety, tolerability and efficacy of flexibly-dosed SPRAVATO (28, 56 or 84 mg) plus a newly initiated oral AD in patients with TRD. During the IND phase (initial 4 weeks), patients self-administered SPRAVATO+AD 2 times per week. In the OP/MA phase (up to 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.

Mean changes in CADSS total score 40-minute postdose for patients are as follows²⁸:

• IND phase: Decreased from 6.4 (day 1) to 3.0 (day 25)
• OP/MA phase: Decreased from 2.8 (week 1) to 1.0 (week 48)

Incidence of Dissociation in Other Phase 3 Studies

SUSTAIN-3 (3008)³²  was an open-label extension study to evaluate the long-term safety and efficacy of individualized, intermittently dosed SPRAVATO+oral AD in patients with TRD (N=1148). During the IND phase (initial 4 weeks), patients self-administered a flexible dose of SPRAVATO 2 times per week (starting dose of 28 mg [patients aged ≥65 years], 56 mg, or 84 mg). In the OP/MA phase (variable duration), patients were administered SPRAVATO once weekly, every other week, or every 4 weeks based on severity of depression symptoms.

Dissociation was reported in 25.5% (293/1148) of patients and led to discontinuation of SPRAVATO in 0.4% (5/1148) of patients. Overall, 99.8% of dissociation events occurred and resolved on the dosing day, in 3.1% (36/1148) of patients, the dissociation events persisted for more than 2 hours. No serious dissociation AEs were reported.

ESCAPE-TRD³³ was a 32-week, randomized, phase 3b study that evaluated the efficacy and safety of SPRAVATO vs quetiapine extended-release (QUE-XR) in combination with ongoing oral AD (selective serotonin reuptake inhibitor [SSRI] or serotonin norepinephrine reuptake inhibitor [SNRI]) in patients with TRD. In the treatment phase (initial 8 weeks), patients were randomized to receive flexible doses of SPRAVATO+oral AD (28 mg, 56 mg, or 84 mg SPRAVATO) or QUE-XR+oral AD (50 mg on day 1, increasing to 150-300 mg/day QUE-XR); flexible dosing was continued for 24 weeks in the MA phase.³⁴ 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 9-32.³⁴

Dissociation was reported in 28.1% (94/334) of patients in the SPRAVATO group and 0.6% (2/336) in the QUE-XR group.³⁴ Treatment discontinuation due to dissociation was reported in 0.6% (2/334) of patients in the SPRAVATO group and none in the QUE-XR group.³⁴

Chen et al (2023)³⁵ conducted a randomized, DB, active-controlled, multicenter study in patients with TRD aged 18-64 years in China and the US to evaluate the efficacy and safety of flexibly dosed (56 or 84 mg) SPRAVATO+oral AD (n=126) vs PBO+oral AD (n=126) after 4 weeks of treatment. Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under the supervision of clinical staff. A new open-label oral AD was initiated (duloxetine, escitalopram, sertraline, or venlafaxine extended release).

Dissociation was reported in 59.5% (75/126) of patients in the SPRAVATO group vs 6.3% (8/126) in the PBO group. Treatment-emergent dissociation leading to treatment discontinuation was reported in 1.6% (2/126) of patients treated with SPRAVATO. In both groups, all treatment-related dissociation that occurred on the day of dosing resolved on the same day. Over the course of the study, the peak mean CADSS total score at the 40-minute timepoint in patients treated with SPRAVATO decreased with consecutive doses.³⁶

Monotherapy Study

Janik et al (2025)¹² conducted a phase 4, doubleblind, randomized, placebocontrolled, multicenter study in adults with TRD in the US to evaluate the efficacy and safety of fixeddose SPRAVATO (56 mg or 84 mg) monotherapy vs intranasal placebo over a 4week doubleblind period. Participants selfadministered the study drug twice weekly under clinical supervision. The study also included a subsequent 12week openlabel treatment phase in which all participants received SPRAVATO regardless of the treatment received during the previous phase.

During the doubleblind phase, dissociation occurred in 24.3% (55/226) of patients receiving SPRAVATO vs 2.8% (7/250) of patients receiving placebo. Of those who received 56 mg and 84 mg, 21.9% (23/105) and 26.4% (32/121) experienced dissociation, respectively. In the openlabel phase, dissociation was observed in 15.6% (69/441) of SPRAVATOtreated patients overall, including in 17.7% of those who were transitioned from placebo to SPRAVATO.

Post Hoc Analysis of Tolerability Trends During Postdose Monitoring

Williamson et al (2022)¹¹ conducted a post hoc for the 2 long-term studies^5,6 that characterized 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.¹¹

Results

Dissociation was reported in 16.7% of patients in week 1, (see Table: Rates of Dissociation Recurrence According to Frequency of Dissociation Occurrence in Week 1). Compared with week 1, the dissociation occurrence in week 4 was more closely associated with later recurrence.

The mean severity score was 1.2-1.4 in patients who reported mild-to-moderate levels of dissociation per CADSS (total score ≤14); no obvious difference was reported in the severity of subsequent episodes of dissociation. The mean severity score was 1.3-2.1 in patients with maximum CADSS scores (15-24 and 24-42) across all time frames.¹¹

Post Hoc Analysis of SUSTAIN-2

Ochs-Ross et al (2021)¹⁶ performed a post hoc analysis of the long-term (1-year), openlabel, multicenter, phase 3 SUSTAIN-2 study comparing the efficacy and safety of SPRAVATO nasal spray in younger (18-64 years) vs older (≥65 years) patients with TRD. In younger vs older patients, the incidences of dissociation occurred in 24.0% (150/624) vs 20.6% (32/155) of patients during the IND phase and in 19.3% (92/477) vs 16.7% (21/126) of patients during the OP/MA phase. The greatest mean postdose increase in CADSS total score (at 40 minutes) after the first SPRAVATO dose was higher in younger patients. The incidence of dissociation (CADSS total score >4) was similar between both age groups.

Post Hoc Analysis of ASPIRE Studies

Fua et al (2020)³⁷ performed a post hoc analysis of patients with MDD and active suicidal ideation with intent (pooled data from ASPIRE I and ASPIRE II trials), which found 33.9% of patients (77/227) who had received SPRAVATO+SOC and 5.8% of patients (13/225) who had received PBO+SOC experienced dissociation. Severe dissociation occurred in 4.0% of patients (9/227) who received SPRAVATO+SOC and in no patients who received PBO+SOC. Discontinuations due to dissociation of any severity occurred in 1.3% of patients (3/227) who received SPRAVATO+SOC and in no patients who received PBO+SOC.

Post Hoc Analyses Evaluating the Relationship Between Dissociation and Efficacy

Chen et al (2022)¹³ performed a post hoc analysis of patients with TRD (data from TRANSFORM-2 and SUSTAIN-1 studies), which did not find a significant association between the presence of dissociation and efficacy of SPRAVATO. Correlation analyses in TRANSFORM2 showed that there were no significant associations between increases in CADSS total scores after first nasal spray treatment and improvements in depressive symptoms on either day 2 (r=-0.05 [95% confidence interval (CI), -0.23 to 0.14]) or day 28 (r=-0.08 [95% CI, -0.27 to 0.12]), or between increases in CADSS total score after the last nasal spray treatments on day 25 and improvements in depressive symptoms on day 28 (r=-0.16 [95% CI, -0.36 to 0.04]). Similar findings resulted from analyses of the TRANSFORM-1 study.

A mediation analysis of TRANSFORM-2 showed insufficient mediation effects of dissociation on SPRAVATO efficacy on day 1 (least-squares mean difference [LSMD]: -0.45; 95% CI, 1.85 to 0.85) and on day 25 (LSMD: -0.42; 95% CI, -1.95 to 0.94) of treatment. In contrast, SPRAVATO had a significant and direct effect on depressive symptoms on day 1 (LSMD: -3.62; 95% CI, -6.62 to -0.74) and day 25 (LSMD: -4.83; 95% CI, 8.37 to 1.28). Similarly, the mediation analysis for SUSTAIN-1 showed a lack of mediation of dissociation on the time to relapse after SPRAVATO treatment in the MA phase (LSMD: 0.12; 95% CI, -3.22 to 3.45] but a significant effect of SPRAVATO on the time to relapse (LSMD: -2.44; 95% CI, -4.04 to -0.84).

In TRANSFORM-2, mean peak CADSS total scores significantly decreased over time following consecutive SPRAVATO treatments where fewer patients experienced significant dissociation, whereas the antidepressant effect of SPRAVATO was maintained without significant between-group changes in Montgomery and Asberg Depression Rating Scale (MADRS) total scores. The authors suggest further research is needed to understand the N-methyl-Daspartate receptor (NMDAR) antagonist mechanism and pathway that mediates the antidepressant effect relative to the dissociative effects of SPRAVATO.

A similar post hoc analysis of TRANSFORM-1 and TRANSFORM-2 came to the same conclusion, that is, there was no clinically significant positive or negative association between dissociation and antidepressant effect for SPRAVATO.³⁸

A post hoc analysis of data from ASPIRE I and ASPIRE II trials came to the same conclusion, that is, there was no clinically significant association between the presence of dissociation and efficacy of SPRAVATO. The presence of dissociation was measured by CADSS >4 on day 1 and response rate was defined as >/=50% improvement on the MADRS on day 2. A similar proportion of patients responded in the cohort who experienced dissociation and those who did not (33.8% and 39.1%, respectively). Findings were consistent when response rates were examined in those whom dissociation was reported as an AE. ³⁹

Real-World Retrospective Studies

POSTMARKETING SAFETY DATA

REMS and US-GMS Database

REMS patient monitoring forms completed by certified US healthcare settings and pharmacies from 5 March 2019 to 5 January 2024, identified 58,483 patients who received ≥1 SPRAVATO treatment session. Dissociative effects were reported in 65.7% of patients in 41.0% of treatment sessions. The number of dissociation events appeared higher during the first treatment session (46.9 events per 100 administrations) versus the entire induction and early maintenance phase (43.5 and 41.2 events per 100 administrations, respectively), and it was consistent across sexes and age groups (<25 years, 25-55 years, and >55 years). Dissociation resolved at a median time of 60 minutes based on REMS patient monitoring forms. Based on the number of SAEs (N=3985) in the US-GMS database (database that includes AEs from REMS and other sources), dissociation occurred in 2.2% (n=90) of events.²³

FAERS

A FAERS database analysis (Q3 2014 – Q4 2024) identified 1217 dissociation events (15.6%) among 7790 SPRAVATO-related AEs, showing a markedly elevated reporting odds ratio (ROR) for SPRAVATO (1093.46; 95% CI, 1012.06-1181.41) vs all the other drugs in the database. Dissociation reports were more frequently submitted for men than for women (relative ROR, 1.26) and for older adults (≥65 years old; relative ROR, 3.38). Dissociative disorder was also more likely to be reported in older adults (relative ROR, 10.07)²⁴

Limitations of the FAERS database include the inability to infer causality, barriers to reporting, limitations in the quality of information received, and the inability to calculate the incidence rates of the events.⁴⁰

EudraVigilance (European Pharmacovigilance Database)

An analysis of the EudraVigilance database (2019-2024) identified 751 AEs were related to SPRAVATO; of these events, 265 were serious and 15.8% were dissociation/dissociative disorder events. These reports were more common in women (66.6% [n=33]) than in men (33.3% [n=14]) and occurred primarily in adults aged 18 to 64 years (17.6% [n=37] of serious cases). The incidence rate was not calculable due to limitations of spontaneous reporting data.²⁵

Management of Dissociative Symptoms

Across phase 3 trials of SPRAVATO in TRD (3 short-term trials and 3 long-term trials),^2-6,41 17 patients received a medication for treatment of agitation or anxiety due to dissociation.

• TRANSFORM-1: 3/115 patients treated with SPRAVATO 56 mg+AD and 2/116 patients treated with SPRAVATO 84 mg+AD in the DB phase⁴²
• TRANSFORM-2: 2/115 patients in the DB phase⁴³
• SUSTAIN-2: 1/779 patients in the IND phase and 2/603 patients in the OP/MA phase⁴⁴
• SUSTAIN-3: 7/1148 patients in the IND and OP/MA phases.⁴¹

There were no medications utilized specifically for the management of dissociation. For agitation or anxiety, oral or intramuscular midazolam or another short-acting benzodiazepine was considered.^3,5,42,44,45 Clinical judgment should be used for managing severe dissociation that does not resolve by itself during the postadministration monitoring period.

In a post hoc analysis of patients with MDD with suicidal ideation (MDSI) (pooled data from the ASPIRE I and ASPIRE II trials; see details from Fua et al [2020]), 1 patient from the SPRAVATO+SOC group received a single dose of diazepam in response to symptoms related to severe dissociation.³⁷

Pereira et al (2020)⁴⁶ describe a case of a 64-year-old female patient whose symptoms of confusion, agitation, and anxiety, due to the dissociation she experienced after SPRAVATO administration, were alleviated while listening to music. Symptoms of dissociation, agitation, and confusion appeared shortly after the first dose and she continued to experience them in subsequent sessions. After the third treatment session, the patient asked to listen to music on her phone to distract her from the dissociative symptoms. Five minutes after listening to music, the patient appeared visibly calmer and was no longer confused or agitated by the dissociation. This strategy was successful in managing her dissociative symptoms during all subsequent visits. The authors suggest music along with other nonpharmacological ways to manage dissociative symptoms, including providing reassurance that patients are safe and adjusting room temperature and lighting, according to patient preference.

Ceban et al (2021)⁴⁷ recommend nonpharmacological approaches such as creating an environment that feels safe and comfortable in a room that is dimly lit with blankets and calming music. If permitted, they also suggest having a trusted family member or friend be present during treatment.

Hauser et al (2024)⁴⁸ conducted a retrospective observational study in 37 patients to evaluate the effect of music on AEs (including dissociation) during treatment with ketamine, which included a small number of patients treated with SPRAVATO (n=6). Multivariate comparisons between the music-listening and non-music-listening treatment sessions found that music worsened the degree of depersonalization (albeit only by a mean difference of +0.6 points) but had no significant effect on the other Dissociation Symptom Scale-IV items (i.e., somatoform dissociation, derealization, and pain perception).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 25 December 2025. This response contains information limited to the intranasal formulation of esketamine.

Case reports and case series, except the ones reporting management of dissociative symptoms, pediatric studies, real-world studies with <50 patients treated with SPRAVATO were excluded.